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Review

Roles of the NR2F Family in the Development, Disease, and Cancer of the Lung

by
Jiaxin Yang
1,2,
Wenjing Sun
2 and
Guizhong Cui
1,2,*
1
Department of Basic Research, Guangzhou National Laboratory, Guangzhou 510005, China
2
School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
*
Author to whom correspondence should be addressed.
J. Dev. Biol. 2024, 12(3), 24; https://doi.org/10.3390/jdb12030024
Submission received: 21 April 2024 / Revised: 24 August 2024 / Accepted: 30 August 2024 / Published: 10 September 2024
(This article belongs to the Special Issue The 10th Anniversary of JDB: Feature Papers)
Browse Figures
Versions Notes

Abstract

:
The NR2F family, including NR2F1, NR2F2, and NR2F6, belongs to the nuclear receptor superfamily. NR2F family members function as transcription factors and play essential roles in the development of multiple organs or tissues in mammals, including the central nervous system, veins and arteries, kidneys, uterus, and vasculature. In the central nervous system, NR2F1/2 coordinate with each other to regulate the development of specific brain subregions or cell types. In addition, NR2F family members are associated with various cancers, such as prostate cancer, breast cancer, and esophageal cancer. Nonetheless, the roles of the NR2F family in the development and diseases of the lung have not been systematically summarized. In this review, we mainly focus on the lung, including recent findings regarding the roles of the NR2F family in development, physiological function, and cancer.

1. Introduction

Nuclear receptors (NRs), a family of evolutionarily conserved proteins, are ligand-activated transcription factors that participate in the regulation of both physiological and pathological processes [1]. In humans, 48 NRs have been identified, including receptors for steroid hormones, thyroid hormones, cholesterol metabolites, and lipophilic vitamins. NRs are categorized into seven classes: Class 0: miscellaneous; Class I: thyroid hormone receptor-like; Class II: retinoid X receptor-like; Class III: estrogen receptor-like; Class IV: nerve growth factor IB-like; Class V: steroidogenic factor-like; Class VI: germ cell nuclear factor-like [2]. NRs share common structural characteristics, including a transactivation region, a central DNA-binding domain, a region responsible for nuclear localization, and a ligand-binding domain. They function as transcription factors and regulate the expression of genes involved in metabolism, fertility, immunity, angiogenesis and other biological processes [3]. The Nuclear Receptor Subfamily 2 Group F (NR2F) family belongs to Class II of the nuclear receptor superfamily. Due to the lack of identified endogenous ligands, NR2F family members are also known as orphan nuclear receptors.
In humans, the main members of the NR2F family include NR2F1, NR2F2, and NR2F6. NR2F1 and NR2F2 are also named COUP-TFI (Chicken Ovalbumin Upstream Promoter Transcription Factor I) and COUP-TFII (Chicken Ovalbumin Upstream Promoter Transcription Factor II), respectively [4,5,6]. NR2F1 and NR2F2 contain two highly conserved domains, the DNA-binding domain and the ligand-binding domain. NR2F1 and NR2F2 are highly conserved across vertebrate species (in many cases, the conserved subdomains exceed 95% homology) [5]. In general, the NR2F family members exert their functions through two major mechanisms. One is direct regulation by binding to DNA elements, including direct repeat-1, which directly suppresses or activates the expression of target genes. The other mechanism is indirect regulation by interacting with transcription factors such as SP1 to activate the expression of target genes [7,8,9]. NR2F family members perform regulatory functions by forming homodimers or heterodimers. In addition to self-dimerization, NR2F family members also competitively bind with other nuclear receptors, such as retinoic X receptors (RXRs), to inhibit the function of other nuclear receptors [10]. Consequently, several nuclear receptors, such as thyroid hormone receptors (TRs) and retinoic acid receptors (RARs), have been shown to have crosstalk with NR2F family members [10,11].
Previous studies have shown that the NR2F family plays pivotal roles in mammalian embryonic development. For example, in the central nervous system (CNS), Nr2f1 orchestrates the regionalization of neocortex [12]; meanwhile, both Nr2f1 and Nr2f2 are involved in the development of cortical interneurons and the generation of the dorsal–ventral axis of the hippocampus [13,14,15]. Moreover, several studies have demonstrated that mutations in NR2F1 lead to Bosch–Boonstra–Schaaf optic atrophy syndrome (BBSOAS), which has various symptoms, such as optic atrophy, autism, mental retardation and epilepsy [16,17,18]. It is noteworthy that Nr2f1 and Nr2f2 often have a complementary effect on neuronal development. Additionally, Nr2f2 regulates vasculogenesis in the heart and spinal cord, as well as the development of the kidney, stomach, and diaphragm [19,20,21]. Nr2f6 is involved in adipocyte differentiation, and it is also considered an essential factor in immune checkpoint regulation to manipulate the development and physiological functions of immune cells [22,23].
Numerous reports have suggested that the NR2F family members are highly involved in cancer, including breast cancer, prostate cancer, and liver cancer [24,25,26,27,28]. Dysregulated long noncoding RNAs associated with the NR2F family have been identified in cancers. For example, NR2F1 interacted with NR2F1-AS1 to activate the Sonic Hedgehog signaling pathway and promote the progression of esophageal squamous cell carcinoma [29]. The functions of the NR2F family in CNS development have been reviewed [17,30]. Nevertheless, the roles of the NR2F family in cancer occurrence and progression still lack in-depth studies and systematic summaries. In this review, we summarize the current understanding of the NR2F family in lung development and pathological conditions, proposing an updated and critical view of the various functions of NRs.

2. NR2F Family in Lung Development and Non-Cancerous Diseases

In mice, lung development begins at E9.0. By E9.5, lung progenitors form the trachea and buds, progressing through stages to generate functional lungs [31] (Figure 1a). Multiple genes regulate lung development. For instance, Fgf10 regulates early branching morphogenesis [32,33,34]. Sox2 and Sox9/Id2 dominate the proximal–distal axis patterning. Proximal cells with high Sox2 expression develop into neuroendocrine cells and non-neuroendocrine cells, while distal cells with high Sox9/Id2 expression give rise to type I and type II alveolar cells. Alveolar cells are responsible for gas exchange, morphology maintenance, and surfactant secretion [31,35,36]. Abnormalities in terms of lung development can cause diseases like bronchopulmonary dysplasia [37].
Previous studies have demonstrated that NR2F2 is widely expressed in the developing lung [38]. With advancements in single-cell RNA sequencing and the stem cell-derived organoid system, NR2F1 has been shown to be expressed in the foregut and developing lung epithelium and mesenchyme [39]. Both blood vessels and lymph vessels are essential components of the lung mesenchyme. Recent studies suggest that the NR2F family may play critical roles in lung angiogenesis and lymphangiogenesis. NR2F1 and NR2F2 have been identified as lymphatic marker genes, with NR2F2 specifically marking venous endothelial cells [40] (Figure 1b). Additionally, NR2F1 has been suggested in a BioRx preprint to be one of the genes involved in the core organ-size regulation program, displaying a unique expression pattern in the developing swine lung epithelium and mesenchyme [41]. In the lung epithelium, the expression of NR2F1 is restricted to the initial stages of lung development, whereas it is almost absent in later stages. In contrast, in the lung mesenchyme, NR2F1 is continuously expressed throughout development. Furthermore, a function of Nr2f1 in the growth and differentiation of ciliated bronchial epithelium was uncovered in a study evaluating the role of Pten overexpression in lung cancer [42]. Pten overexpression blocked this function of Nr2f1. These authors also found that Nr2f1 upregulated other ciliogenesis-related genes, including Mucin5a, DNAI2, and DNAI3 (Figure 1c). Despite some progress in understanding the role of the NR2F family in lung development, the regulatory mechanisms remain largely unexplored. Nonetheless, the association of the NR2F family with various lung-related diseases underscores its significant functions in the lung.
Congenital diaphragmatic hernia (CDH) is a severe lung-related developmental disease with an incidence rate of approximately 1/3000 and a mortality rate exceeding 30%. Several studies suggest that NR2F2 deficiency induces CDH [21,43]. Moreover, pulmonary fibrosis is a progressive lung disease characterized by fibrosis and scar formation in the distal lungs. Idiopathic pulmonary fibrosis (IPF) is the most common form of pulmonary fibrosis without effective treatment available to date. Several studies demonstrated that Nr2f2 can affect IPF by influencing downstream genes such as Col1a1 and Fn1, inhibiting the activation of fibroblasts and the production of extracellular matrix, and enhancing the dissolution of fibrosis [44,45]. Lymphangioleiomyomatosis (LAM), another lung disease, is characterized by abnormal proliferation of smooth muscle, which leads to the obstruction of pulmonary bronchioles and lymphatics, as well as lung function impairment, including pneumothorax. Recent research indicates the potential roles of NR2F2 in the progression of LAM due to its overexpression in tumor tissues [46].

3. NR2F Family in Primary Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Lung cancer can be categorized into small-cell lung cancer and non-small-cell lung cancer (NSCLC). Small-cell lung cancer, characterized by rapid growth and high metastatic potential, is less common but predominantly found in smokers, with most patients exhibiting TP53 mutations [47,48,49]. NSCLC, which accounts for over 85% of all lung cancer cases, can be further classified into lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and large cell carcinoma. LUSC and LUAD have been prevalent and extensively studied [47]. LUSC originates mainly from the internal epithelial cells of the bronchi or bronchioles, and it is characterized by a squamous cell morphology, keratinization, and the presence of intercellular bridges [50]. LUAD arises from glandular cells with secretory functions in the lungs and exhibits diverse morphological features, and it can be identified by NKX2.1 expression or Napsin-A staining [47].
Studies on LUAD have found that the overexpression of NR2F1 can enhance the migration and invasion of tumor cells, probably through NR2F1-AS1, which is upregulated by NR2F1 and ZEB1 [51]. Intriguingly, the overexpression of NR2F2 in lung tumor cells also enhances their invasion and migration capabilities by in vitro modeling [52]. Furthermore, NR2F2 is regulated by the Wnt signaling pathway to activate the expression of GPX4, which could induce high glutathione (GSH) consumption to inhibit ferroptosis and lead to the drug resistance of lung cancer cells that metastasize to the brain [53]. Additionally, NR2F6 expression is significantly upregulated in LUAD tissue [54], and the single nucleotide variation of NR2F6 is strongly related to the survival rate of patients in the early stage of NSCLC [55]. These results from lung and other tissue cancer studies suggest that NR2F6 plays important roles in immunity, metabolism, and the reaction of T cell responses to inflammatory cytokines, such as IL2 and TNFβ, which mediate anti-cancer immune reactions [23,56] (Table 1).

4. NR2F Family in Metastatic Lung Cancer

Most cancer-related deaths result not from the primary tumor itself but from metastatic dissemination [60]. In the later stages of cancer, primary tumor cells undergo transformation, then travel to distant sites, and re-establish tumor clones. Almost any cancer can spread to the lungs since all blood must pass through the lungs during oxygenation and any circulating tumor cell could be filtered out in its rich capillary network. Many cancer patients in advanced stages are often discovered to have lung lesions, particularly in patients with breast and colon cancer, which are highly prone to lung metastasis. The late-stage metastasis of tumor cells is an important factor contributing to the challenge of the treatment and the high mortality rate. The process of tumor cell metastasis to the lungs involves several stages, including tumor cells detaching from the primary tumor tissue, infiltrating surrounding tissues, invading the blood or lymphatic vessels, entering the lungs through the bloodstream and lymphatics, extravasating from the vessels, colonizing in lung tissue, initiating growth, and eventually forming metastatic lung cancer [61,62].
During tumor cell metastasis, several crucial biological processes unfold, including reshaping of the tumor microenvironment (TME), transformation of the tumor cell status, and the dormancy and activation of tumor cells [61,62,63,64]. Reshaping the TME primarily involves the activation of inflammatory responses, increased angiogenesis, and immune suppression [63]. The transformation of the tumor cell status includes the transition of tumor cells from an epithelial cell state to a mesenchymal cell state, known as epithelial–mesenchymal transition (EMT), during the initial stages of metastasis, facilitating migration and invasion. Subsequently, upon reaching distant organs via the bloodstream, tumor cells may undergo mesenchymal–epithelial transition (MET), reverting to an epithelial state to support rapid proliferation [61,62,63]. Upon initial arrival in the lungs, tumor cells often enter a period of dormancy before being reactivated, which is possibly related to the establishment of a new niche of tumor cells in the lungs, and it is also a significant reason why many cancer patients experience recurrence after undergoing curative treatment [61,64].
Studies using animal models of metastatic lung cancer indicate that elevated NR2F1 expression in tumor cells can induce dormancy in lung tissues by co-regulating with SMAD4 and TGFβ, causing tumor cells to exit the cell cycle [65]. Similarly, NR2F1-AS1 upregulates NR2F1 expression to suppress ΔNp63 expression and prevent the MET process in tumor cells, leading to reduced proliferation of breast cancer cells that have metastasized to the lungs [66].
In both human tissues and cellular models, NR2F1 suppresses the metastasis of salivary adenoid cystic carcinoma (SACC) tumor cells to the lungs by upregulating the CXCL12/CXCR4 pathway [67]. Nr2f2 modulates the metastasis of breast tumor cells to the lungs by activating the expression of Ang1, thereby promoting tumor angiogenesis, facilitating the provision of nutrients and oxygen to support tumor cell metastasis to the lungs [24]. Additionally, reports on gastric cancer with lung metastases have discovered that Fbxo21 inhibits EMT by suppressing Nr2f2 in both in vivo tissues and in vitro cell lines [68]. These findings underscore the involvement of the NR2F family in the metastatic processes of various tumor cells in relation to the lungs, which could indicate its significance in the progression of metastatic lung cancer (Table 2).

5. Other Members of the Nuclear Receptor Superfamily Associated with the NR2F Family and Lung Cancer

In addition to the NR2F family, there are more than 40 members of the nuclear receptor superfamily [70], many of which play important roles in organ development and homeostasis, including the lungs. These nuclear receptors actively regulate various cellular functions; in addition, the expression levels of many nuclear receptors, such as progesterone receptor (PR), have been identified as prognostic factors for lung cancer patients [71,72]. The NR2F family members either interact with other nuclear receptors, such as RXRs, to form heterodimers or compete with other nuclear receptors for the binding sites of target genes to mutually regulate their functions [10]. Therefore, summarizing the roles of other nuclear receptors in lung cancer can provide further insights into their interaction mechanisms with the NR2F family (Figure 2).

5.1. Estrogen Receptors (ERs)

ERs belong to Cass III of the nuclear receptor superfamily and serve as receptors for the steroid hormone estrogen. ERs, including two subtypes ERα and ERβ, play essential roles in normal cell growth, differentiation, and survival [70]. Several reports have revealed a close association between ERs and NR2F2 expression. NR2F2 is highly expressed in ER-positive breast cancer cell lines but is poorly expressed in ER-negative breast cancer cell lines [73]. Additionally, Nr2f1 can also modulate the activity of ERs [74]. Studies in non-small-cell lung cancer have shown the dynamic expression of ERs, indicating that ERs could potentially have diverse functions in the genesis and progression of lung cancer [75,76,77,78]. Treatment with ER agonists have been found to increase the proliferation of lung tumor cells in animal models, while ER antagonists inhibit cell growth through IL-6 [79].

5.2. Progesterone Receptor (PR)

Similar to ERs, PR belongs to Class III of the nuclear receptor superfamily and is a receptor for progesterone. PR has two isoforms, PR-A and PR-B, which form homodimers or heterodimers to bind to the progesterone response elements (PREs) on DNA and to regulate the expression of target genes [80]. In breast cancer cell lines, PR and ERs collaborate to downregulate the transcription of NR2F1-AS1 [81]. During embryonic implantation, PR regulates the expression of NR2F2 by controlling Indian Hedgehog, which can activate NR2F2, then NR2F2 inhibits ERs in the uterine epithelium [82]. Several studies have shown a significant decrease of PR in lung cancer tissues [83], and similar results were observed in a mouse model with lung tumor cells transplanted [84], suggesting that PR could be a potential target for lung cancer treatment.

5.3. Retinoic Acid Receptors (RARs)

RARs belong to Class I of the nuclear receptor superfamily and act as receptors for retinoic acid. RARs, which can be classified into three subtypes, RARα (NR1B1), RARβ (NR1B2), and RARγ (NR1B3), regulate cell proliferation, differentiation, and death [70]. Previous studies indicated that the NR2F family members inhibit the target gene regulation of RARs [10]. Intriguingly, NR2F1/2 can be activated by RA signals [85]. In turn, NR2F2 induces the expression of RARβ through RA and RARα [86]. RARβ is considered a tumor suppressor in epithelial cells [87,88]. For example, the expression of RARβ was downregulated in lung tumor tissues, suggesting a potential tumor-suppressive role of RARβ [89,90,91]. Nevertheless, the upregulation of RARβ is also observed in lung cancer tissues [92]. Therefore, further investigation into the roles of RARs and their potential interactions with the NR2F family in lung cancer is warranted.

5.4. Retinoic X Receptors (RXRs)

RXRs belong to Class II of the nuclear receptor superfamily and serve as receptors for 9-cis-retinoic acid. RXRs are mainly divided into RXRα (NR2B1), RXRβ (NR2B2), and RXRγ (NR2B3), and RXRγ can further be subdivided into RXRγ1 and RXRγ2 [93]. RXRs can form heterodimers with several nuclear receptor families, including the NR2F family [10,94]. Studies have shown the downregulation of RXRs in lung cancer tissues [95]. Treatment with RXRs agonists, such as bexarotene, inhibits tumor angiogenesis, suppresses the proliferation and migration of lung tumor cells, and promotes tumor cell death through the PPARγ, PTEN, and mTOR pathways [96].

5.5. Peroxisome-Proliferator-Activated Receptors (PPARs)

PPARs belong to Class I of the nuclear receptor superfamily and are receptors for fatty acids. PPARs have three subtypes: PPARα, PPARβ, and PPARγ. They form heterodimers to bind onto the peroxisome proliferator response elements (PPREs) on target genes. PPARs are prominently expressed in adipocytes, and the Wnt/β-catenin signaling pathway can increase the expression of NR2F2 to inhibit PPARγ expression, leading to the suppression of adipogenesis [97]. In addition, a significant decrease of PPARγ expression was reported in lung cancer research [98]. Treatment with PPARγ ligands in adenocarcinoma cell lines inhibits cell proliferation, suggesting that PPARγ ligands hold promise as potential therapeutic agents [99].

5.6. Vitamin D Receptors (VDRs)

Vitamin D is synthesized by cells of the immune system and plays a critical role in anti-proliferative activities in cancer cells, such as breast, colon, and stomach tumor cells. VDRs are steroid hormone receptors that induce a cascade of cell signaling to maintain healthy Ca2+ levels, which serve to control several biological processes. The NR2F family may compete with VDRs to bind to elements of the VDRs, such as DR3, on their target genes to inhibit the activity of VDRs [10]. The expression levels of VDRs in lung cancer tissues are higher than those in non-cancerous tissues [100]. The expression of VDRs was also associated with improved survival in another lung cancer study [101], suggesting that the dysregulation of VDRs may interact with the NR2F family, leading to malignant transformation in the lungs.

5.7. Thyroid Hormone Receptors (TRs)

TRs belong to Class I of the nuclear receptor superfamily and act as receptors for thyroid hormone. TRs consist of two subtypes, TRα and TRβ, which are important regulators of many fundamental physiological processes, including development, growth, and metabolism. The NR2F family inhibits the activities of TRs on their target genes by competing for the TRs’ binding sites [10]. TRα is significantly higher expressed in LUSC than in LUAD, indicating that it may play a dominant role in LUSC [102]. Intriguingly, both types of lung cancer patients exhibit the loss of TRβ expression [103], demonstrating that TRs play diverse roles in different subtypes of lung cancer.

6. Discussion

The NR2F family not only plays a role in lung development but also contributes to various lung-related diseases, such as CDH, IPF, and lymphangioleiomyomatosis. Moreover, the NR2F family is essential for the progression of both primary lung cancer and metastatic lung cancer. In primary lung cancer, NR2F1 and NR2F2 influence the migration and invasion of tumor cells, while NR2F6 acts as an immune checkpoint factor to modulate immune processes. In metastatic lung cancer, NR2F1 mainly inhibits the transition of dormant tumor cells to a proliferative state in the lungs, while NR2F2 influences tumor cell metastasis to the lungs by affecting the tumor microenvironment, such as angiogenesis or EMT. NR2F1-AS1 is closely linked to NR2F1-related functions in the progress of lung cancer. Previous studies have provided some preliminary insights into the regulatory mechanisms of the NR2F family in lung cancer and other lung diseases; nonetheless, how the NR2F family participates in the regulation of the tumor microenvironment in lung cancer is still largely unclear. The roles of lung cancer-related genes, such as KRAS, EGFR, and ALK, have been systematically investigated in specific animal models of cancers [104]. However, previous studies on the NR2F family in the lungs have mostly been conducted using lung cancer cell lines or clinical tissue samples. The generation of specific lung cancer animal models for NR2F1, NR2F2, and NR2F6 will not only enhance the understanding of the molecular mechanisms of lung cancer but also improve the diagnosis and therapy for lung cancer associated with NR2F family dysregulation.
Previous studies have demonstrated that nuclear receptors are excellent targets for cancer therapy. Currently, drugs against nuclear receptors, such as ER and RXR, have been developed and used to treat various cancers, including breast cancer, with convincing efficacy [105]. The NR2F nuclear receptor subfamily, which interacts with various nuclear receptors, including RARs and RXRs, is a potential novel therapeutic target in cancer, especially in lung cancer.
Single-cell and spatial omics technologies are rapidly advancing and have been widely applied to research on development and disease, which enables precise identification of cellular heterogeneity and cell–cell communications. Spatial omics technology, which can simultaneously provide spatial location and omics information of tissues, makes it possible to uncover the interactions among cells in the tumor microenvironment [106]. Recently, spatial omics methods have been used to compare the difference between primary and metastatic tumor tissues in the brain metastasis of NSCLC. Changes in the immune-suppressive and fibrotic microenvironment were identified, and those changes aid the metastatic tumor cells in creating a suitable niche for rapid proliferation and progression in the brain [107].
In summary, the expression and functions of the NR2F family are closely associated with lung development and lung-related diseases. By establishing well-designed animal models targeting the NR2F family members in the lungs and combining the latest technologies, like spatial omics, a better understanding of the molecular and cellular mechanisms of the NR2F family in the development and diseases of the lung may be achieved, which will benefit the findings of novel diagnostic and therapeutic approaches for NR2F-related lung diseases, including lung cancer.

Author Contributions

J.Y. and G.C. conceptualized the subject, reviewed the literature, and wrote the draft manuscript. W.S. assisted in the manuscript’s preparation. G.C., J.Y. and W.S. designed the figures, and revised and finalized the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (32100483) and the Major Project of Guangzhou National Laboratory (GZNL2023A02007, GZNL2023A03005).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Guangdun Peng for the discussions, Ke Tang for the helpful feedback on the manuscript, and the anonymous reviewers for the useful suggestions.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Sever, R.; Glass, C.K. Signaling by nuclear receptors. Cold Spring Harb. Perspect. Biol. 2013, 5, a016709. [Google Scholar] [CrossRef]
  2. Parris, T.Z. Pan-cancer analyses of human nuclear receptors reveal transcriptome diversity and prognostic value across cancer types. Sci. Rep. 2020, 10, 1873. [Google Scholar] [CrossRef]
  3. Guzman, A.; Hughes, C.H.K.; Murphy, B.D. Orphan nuclear receptors in angiogenesis and follicular development. Reproduction 2021, 162, R35–R54. [Google Scholar] [CrossRef] [PubMed]
  4. Wang, L.H.; Tsai, S.Y.; Sagami, I.; Tsai, M.J.; O’Malley, B.W. Purification and characterization of chicken ovalbumin upstream promoter transcription factor from HeLa cells. J. Biol. Chem. 1987, 262, 16080–16086. [Google Scholar] [CrossRef] [PubMed]
  5. Wang, L.H.; Ing, N.H.; Tsai, S.Y.; O’Malley, B.W.; Tsai, M.J. The COUP-TFs compose a family of functionally related transcription factors. Gene Expr. 1991, 1, 207–216. [Google Scholar]
  6. Barnhart, K.M.; Mellon, P.L. The sequence of a murine cDNA encoding Ear-2, a nuclear orphan receptor. Gene 1994, 142, 313–314. [Google Scholar] [CrossRef]
  7. Park, J.I.; Tsai, S.Y.; Tsai, M.J. Molecular mechanism of chicken ovalbumin upstream promoter-transcription factor (COUP-TF) actions. Keio J. Med. 2003, 52, 174–181. [Google Scholar] [CrossRef] [PubMed]
  8. Leng, X.; Cooney, A.J.; Tsai, S.Y.; Tsai, M.J. Molecular mechanisms of COUP-TF-mediated transcriptional repression: Evidence for transrepression and active repression. Mol. Cell Biol. 1996, 16, 2332–2340. [Google Scholar] [CrossRef]
  9. Tang, K.; Tsai, S.Y.; Tsai, M.J. COUP-TFs and eye development. Biochim. Biophys. Acta 2015, 1849, 201–209. [Google Scholar] [CrossRef]
  10. Cooney, A.J.; Tsai, S.Y.; O’Malley, B.W.; Tsai, M.J. Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors. Mol. Cell Biol. 1992, 12, 4153–4163. [Google Scholar] [CrossRef]
  11. Kruse, S.W.; Suino-Powell, K.; Zhou, X.E.; Kretschman, J.E.; Reynolds, R.; Vonrhein, C.; Xu, Y.; Wang, L.; Tsai, S.Y.; Tsai, M.J.; et al. Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol. 2008, 6, e227. [Google Scholar] [CrossRef] [PubMed]
  12. Armentano, M.; Chou, S.J.; Tomassy, G.S.; Leingartner, A.; O’Leary, D.D.; Studer, M. COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nat. Neurosci. 2007, 10, 1277–1286. [Google Scholar] [CrossRef] [PubMed]
  13. Lodato, S.; Tomassy, G.S.; De Leonibus, E.; Uzcategui, Y.G.; Andolfi, G.; Armentano, M.; Touzot, A.; Gaztelu, J.M.; Arlotta, P.; Menendez de la Prida, L.; et al. Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy. J. Neurosci. 2011, 31, 4650–4662. [Google Scholar] [CrossRef]
  14. Alzu’bi, A.; Lindsay, S.J.; Harkin, L.F.; McIntyre, J.; Lisgo, S.N.; Clowry, G.J. The Transcription Factors COUP-TFI and COUP-TFII have Distinct Roles in Arealisation and GABAergic Interneuron Specification in the Early Human Fetal Telencephalon. Cereb. Cortex 2017, 27, 4971–4987. [Google Scholar] [CrossRef] [PubMed]
  15. Yang, X.; Wan, R.; Liu, Z.; Feng, S.; Yang, J.; Jing, N.; Tang, K. The differentiation and integration of the hippocampal dorsoventral axis are controlled by two nuclear receptor genes. eLife 2023, 12, RP86940. [Google Scholar] [CrossRef]
  16. Bosch, D.G.; Boonstra, F.N.; Gonzaga-Jauregui, C.; Xu, M.; de Ligt, J.; Jhangiani, S.; Wiszniewski, W.; Muzny, D.M.; Yntema, H.G.; Pfundt, R.; et al. NR2F1 mutations cause optic atrophy with intellectual disability. Am. J. Hum. Genet. 2014, 94, 303–309. [Google Scholar] [CrossRef]
  17. Yang, X.; Feng, S.; Tang, K. COUP-TF Genes, Human Diseases, and the Development of the Central Nervous System in Murine Models. Curr. Top. Dev. Biol. 2017, 125, 275–301. [Google Scholar] [CrossRef]
  18. Zhang, K.; Yu, F.; Zhu, J.; Han, S.; Chen, J.; Wu, X.; Chen, Y.; Shen, T.; Liao, J.; Guo, W.; et al. Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation. Cell Rep. 2020, 31, 107521. [Google Scholar] [CrossRef]
  19. Yu, C.T.; Tang, K.; Suh, J.M.; Jiang, R.; Tsai, S.Y.; Tsai, M.J. COUP-TFII is essential for metanephric mesenchyme formation and kidney precursor cell survival. Development 2012, 139, 2330–2339. [Google Scholar] [CrossRef]
  20. Takamoto, N.; You, L.R.; Moses, K.; Chiang, C.; Zimmer, W.E.; Schwartz, R.J.; DeMayo, F.J.; Tsai, M.J.; Tsai, S.Y. COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development 2005, 132, 2179–2189. [Google Scholar] [CrossRef]
  21. You, L.R.; Takamoto, N.; Yu, C.T.; Tanaka, T.; Kodama, T.; Demayo, F.J.; Tsai, S.Y.; Tsai, M.J. Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc. Natl. Acad. Sci. USA 2005, 102, 16351–16356. [Google Scholar] [CrossRef]
  22. Pelaez-Garcia, A.; Barderas, R.; Batlle, R.; Vinas-Castells, R.; Bartolome, R.A.; Torres, S.; Mendes, M.; Lopez-Lucendo, M.; Mazzolini, R.; Bonilla, F.; et al. A proteomic analysis reveals that Snail regulates the expression of the nuclear orphan receptor Nuclear Receptor Subfamily 2 Group F Member 6 (Nr2f6) and interleukin 17 (IL-17) to inhibit adipocyte differentiation. Mol. Cell Proteom. 2015, 14, 303–315. [Google Scholar] [CrossRef] [PubMed]
  23. Klepsch, V.; Hermann-Kleiter, N.; Do-Dinh, P.; Jakic, B.; Offermann, A.; Efremova, M.; Sopper, S.; Rieder, D.; Krogsdam, A.; Gamerith, G.; et al. Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade. Nat. Commun. 2018, 9, 1538. [Google Scholar] [CrossRef]
  24. Qin, J.; Chen, X.; Xie, X.; Tsai, M.J.; Tsai, S.Y. COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc. Natl. Acad. Sci. USA 2010, 107, 3687–3692. [Google Scholar] [CrossRef]
  25. Qin, J.; Wu, S.P.; Creighton, C.J.; Dai, F.; Xie, X.; Cheng, C.M.; Frolov, A.; Ayala, G.; Lin, X.; Feng, X.H.; et al. COUP-TFII inhibits TGF-beta-induced growth barrier to promote prostate tumorigenesis. Nature 2013, 493, 236–240. [Google Scholar] [CrossRef] [PubMed]
  26. Wang, L.; Long, H.; Zheng, Q.; Bo, X.; Xiao, X.; Li, B. Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression. Mol. Cancer 2019, 18, 119. [Google Scholar] [CrossRef]
  27. Xu, M.; Qin, J.; Tsai, S.Y.; Tsai, M.J. The role of the orphan nuclear receptor COUP-TFII in tumorigenesis. Acta Pharmacol. Sin. 2015, 36, 32–36. [Google Scholar] [CrossRef]
  28. Sajinovic, T.; Baier, G. New Insights into the Diverse Functions of the NR2F Nuclear Orphan Receptor Family. Front. Biosci. 2023, 28, 13. [Google Scholar] [CrossRef]
  29. Zhang, Y.; Zheng, A.; Xu, R.; Zhou, F.; Hao, A.; Yang, H.; Yang, P. NR2F1-induced NR2F1-AS1 promotes esophageal squamous cell carcinoma progression via activating Hedgehog signaling pathway. Biochem. Biophys. Res. Commun. 2019, 519, 497–504. [Google Scholar] [CrossRef]
  30. Bertacchi, M.; Parisot, J.; Studer, M. The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease. Brain Res. 2019, 1705, 75–94. [Google Scholar] [CrossRef]
  31. Herriges, M.; Morrisey, E.E. Lung development: Orchestrating the generation and regeneration of a complex organ. Development 2014, 141, 502–513. [Google Scholar] [CrossRef]
  32. Bellusci, S.; Grindley, J.; Emoto, H.; Itoh, N.; Hogan, B.L. Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 1997, 124, 4867–4878. [Google Scholar] [CrossRef] [PubMed]
  33. Park, W.Y.; Miranda, B.; Lebeche, D.; Hashimoto, G.; Cardoso, W.V. FGF-10 is a chemotactic factor for distal epithelial buds during lung development. Dev. Biol. 1998, 201, 125–134. [Google Scholar] [CrossRef]
  34. Weaver, M.; Dunn, N.R.; Hogan, B.L. Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development 2000, 127, 2695–2704. [Google Scholar] [CrossRef]
  35. Que, J.; Luo, X.; Schwartz, R.J.; Hogan, B.L. Multiple roles for Sox2 in the developing and adult mouse trachea. Development 2009, 136, 1899–1907. [Google Scholar] [CrossRef]
  36. Tompkins, D.H.; Besnard, V.; Lange, A.W.; Keiser, A.R.; Wert, S.E.; Bruno, M.D.; Whitsett, J.A. Sox2 activates cell proliferation and differentiation in the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 2011, 45, 101–110. [Google Scholar] [CrossRef]
  37. Schittny, J.C. Development of the lung. Cell Tissue Res. 2017, 367, 427–444. [Google Scholar] [CrossRef]
  38. Kimura, Y.; Suzuki, T.; Kaneko, C.; Darnel, A.D.; Moriya, T.; Suzuki, S.; Handa, M.; Ebina, M.; Nukiwa, T.; Sasano, H. Retinoid receptors in the developing human lung. Clin. Sci. 2002, 103, 613–621. [Google Scholar] [CrossRef] [PubMed]
  39. Miao, Y.; Tan, C.; Pek, N.M.; Yu, Z.; Iwasawa, K.; Kechele, D.O.; Sundaram, N.; Pastrana-Gomez, V.; Kishimoto, K.; Yang, M.C.; et al. Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids. bioRxiv 2024. [Google Scholar] [CrossRef]
  40. Schupp, J.C.; Adams, T.S.; Cosme, C., Jr.; Raredon, M.S.B.; Yuan, Y.; Omote, N.; Poli, S.; Chioccioli, M.; Rose, K.A.; Manning, E.P.; et al. Integrated Single-Cell Atlas of Endothelial Cells of the Human Lung. Circulation 2021, 144, 286–302. [Google Scholar] [CrossRef]
  41. Shimamura, Y.; Tanaka, J.; Kakiuchi, M.; Sarmah, H.; Miura, A.; Hwang, Y.; Sawada, A.; Ninish, Z.; Yamada, K.; Mori, M.; et al. A developmental program that regulates mammalian organ size offsets evolutionary distance. bioRxiv 2022. [Google Scholar] [CrossRef]
  42. Tran, T.T.T.; Hung, J.J. PTEN decreases NR2F1 expression to inhibit ciliogenesis during EGFR(L858R)-induced lung cancer progression. Cell Death Dis. 2024, 15, 225. [Google Scholar] [CrossRef]
  43. Klaassens, M.; van Dooren, M.; Eussen, H.J.; Douben, H.; den Dekker, A.T.; Lee, C.; Donahoe, P.K.; Galjaard, R.J.; Goemaere, N.; de Krijger, R.R.; et al. Congenital diaphragmatic hernia and chromosome 15q26: Determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization. Am. J. Hum. Genet. 2005, 76, 877–882. [Google Scholar] [CrossRef]
  44. Wang, L.; Li, Z.; Wan, R.; Pan, X.; Li, B.; Zhao, H.; Yang, J.; Zhao, W.; Wang, S.; Wang, Q.; et al. Single-Cell RNA Sequencing Provides New Insights into Therapeutic Roles of Thyroid Hormone in Idiopathic Pulmonary Fibrosis. Am. J. Respir. Cell Mol. Biol. 2023, 69, 456–469. [Google Scholar] [CrossRef]
  45. Li, L.; Galichon, P.; Xiao, X.; Figueroa-Ramirez, A.C.; Tamayo, D.; Lee, J.J.K.; Kalocsay, M.; Gonzalez-Sanchez, D.; Chancay, S.; Bonventre, J.V.; et al. Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis. bioRxiv 2020. [Google Scholar] [CrossRef]
  46. Kim, W.; Giannikou, K.; Dreier, J.R.; Lee, S.; Tyburczy, M.E.; Silverman, E.K.; Radzikowska, E.; Wu, S.; Wu, C.L.; Henske, E.P.; et al. A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis. Eur. Respir. J. 2019, 53, 1900329. [Google Scholar] [CrossRef] [PubMed]
  47. Relli, V.; Trerotola, M.; Guerra, E.; Alberti, S. Abandoning the Notion of Non-Small Cell Lung Cancer. Trends Mol. Med. 2019, 25, 585–594. [Google Scholar] [CrossRef] [PubMed]
  48. Alberti, S.; Nutini, M.; Herzenberg, L.A. DNA methylation prevents the amplification of TROP1, a tumor-associated cell surface antigen gene. Proc. Natl. Acad. Sci. USA 1994, 91, 5833–5837. [Google Scholar] [CrossRef]
  49. Nasr, A.F.; Nutini, M.; Palombo, B.; Guerra, E.; Alberti, S. Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene. Oncogene 2003, 22, 1668–1677. [Google Scholar] [CrossRef]
  50. Sanchez-Danes, A.; Blanpain, C. Deciphering the cells of origin of squamous cell carcinomas. Nat. Rev. Cancer 2018, 18, 549–561. [Google Scholar] [CrossRef]
  51. Kim, E.J.; Kim, J.S.; Lee, S.; Cheon, I.; Kim, S.R.; Ko, Y.H.; Kang, K.; Tan, X.; Kurie, J.M.; Ahn, Y.H. ZEB1-regulated lnc-Nr2f1 promotes the migration and invasion of lung adenocarcinoma cells. Cancer Lett. 2022, 533, 215601. [Google Scholar] [CrossRef]
  52. Navab, R.; Gonzalez-Santos, J.M.; Johnston, M.R.; Liu, J.; Brodt, P.; Tsao, M.S.; Hu, J. Expression of chicken ovalbumin upstream promoter-transcription factor II enhances invasiveness of human lung carcinoma cells. Cancer Res. 2004, 64, 5097–5105. [Google Scholar] [CrossRef]
  53. Liu, W.; Zhou, Y.; Duan, W.; Song, J.; Wei, S.; Xia, S.; Wang, Y.; Du, X.; Li, E.; Ren, C.; et al. Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis. Clin. Transl. Med. 2021, 11, e517. [Google Scholar] [CrossRef]
  54. Jin, C.; Xiao, L.; Zhou, Z.; Zhu, Y.; Tian, G.; Ren, S. MiR-142-3p suppresses the proliferation, migration and invasion through inhibition of NR2F6 in lung adenocarcinoma. Hum. Cell 2019, 32, 437–446. [Google Scholar] [CrossRef] [PubMed]
  55. Yoo, S.S.; Hong, M.J.; Lee, J.H.; Choi, J.E.; Lee, S.Y.; Lee, J.; Cha, S.I.; Kim, C.H.; Seok, Y.; Lee, E.; et al. Association between polymorphisms in microRNA target sites and survival in early-stage non-small cell lung cancer. Thorac. Cancer 2017, 8, 682–686. [Google Scholar] [CrossRef]
  56. Klepsch, V.; Siegmund, K.; Baier, G. Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6. Cancers 2021, 13, 2600. [Google Scholar] [CrossRef] [PubMed]
  57. Doi, T.; Sugimoto, K.; Puri, P. Prenatal retinoic acid up-regulates pulmonary gene expression of COUP-TFII, FOG2, and GATA4 in pulmonary hypoplasia. J. Pediatr. Surg. 2009, 44, 1933–1937. [Google Scholar] [CrossRef] [PubMed]
  58. Zhang, C.; Wu, S.; Song, R.; Liu, C. Long noncoding RNA NR2F1-AS1 promotes the malignancy of non-small cell lung cancer via sponging microRNA-493-5p and thereby increasing ITGB1 expression. Aging 2020, 13, 7660–7675. [Google Scholar] [CrossRef] [PubMed]
  59. Jin, L.; Chen, C.; Huang, L.; Sun, Q.; Bu, L. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4. Open Med. 2022, 17, 87–95. [Google Scholar] [CrossRef]
  60. Jassim, A.; Rahrmann, E.P.; Simons, B.D.; Gilbertson, R.J. Cancers make their own luck: Theories of cancer origins. Nat. Rev. Cancer 2023, 23, 710–724. [Google Scholar] [CrossRef]
  61. Fares, J.; Fares, M.Y.; Khachfe, H.H.; Salhab, H.A.; Fares, Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct. Target. Ther. 2020, 5, 28. [Google Scholar] [CrossRef] [PubMed]
  62. Chaffer, C.L.; Weinberg, R.A. A perspective on cancer cell metastasis. Science 2011, 331, 1559–1564. [Google Scholar] [CrossRef] [PubMed]
  63. Altorki, N.K.; Markowitz, G.J.; Gao, D.; Port, J.L.; Saxena, A.; Stiles, B.; McGraw, T.; Mittal, V. The lung microenvironment: An important regulator of tumour growth and metastasis. Nat. Rev. Cancer 2019, 19, 9–31. [Google Scholar] [CrossRef] [PubMed]
  64. Giancotti, F.G. Mechanisms governing metastatic dormancy and reactivation. Cell 2013, 155, 750–764. [Google Scholar] [CrossRef]
  65. Singh, D.K.; Carcamo, S.; Farias, E.F.; Hasson, D.; Zheng, W.; Sun, D.; Huang, X.; Cheung, J.; Nobre, A.R.; Kale, N.; et al. 5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-beta-SMAD4 signaling. Cell Rep. 2023, 42, 112560. [Google Scholar] [CrossRef]
  66. Liu, Y.; Zhang, P.; Wu, Q.; Fang, H.; Wang, Y.; Xiao, Y.; Cong, M.; Wang, T.; He, Y.; Ma, C.; et al. Long non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and DeltaNp63. Nat. Commun. 2021, 12, 5232. [Google Scholar] [CrossRef] [PubMed]
  67. Gao, X.L.; Zheng, M.; Wang, H.F.; Dai, L.L.; Yu, X.H.; Yang, X.; Pang, X.; Li, L.; Zhang, M.; Wang, S.S.; et al. NR2F1 contributes to cancer cell dormancy, invasion and metastasis of salivary adenoid cystic carcinoma by activating CXCL12/CXCR4 pathway. BMC Cancer 2019, 19, 743. [Google Scholar] [CrossRef]
  68. Jiang, Y.; Liu, X.; Shen, R.; Gu, X.; Qian, W. Fbxo21 regulates the epithelial-to-mesenchymal transition through ubiquitination of Nr2f2 in gastric cancer. J. Cancer 2021, 12, 1421–1430. [Google Scholar] [CrossRef]
  69. Liu, Y.; Chen, S.; Cai, K.; Zheng, D.; Zhu, C.; Li, L.; Wang, F.; He, Z.; Yu, C.; Sun, C. Hypoxia-induced long noncoding RNA NR2F1-AS1 maintains pancreatic cancer proliferation, migration, and invasion by activating the NR2F1/AKT/mTOR axis. Cell Death Dis. 2022, 13, 232. [Google Scholar] [CrossRef]
  70. Weikum, E.R.; Liu, X.; Ortlund, E.A. The nuclear receptor superfamily: A structural perspective. Protein Sci. 2018, 27, 1876–1892. [Google Scholar] [CrossRef]
  71. Gangwar, S.K.; Kumar, A.; Yap, K.C.; Jose, S.; Parama, D.; Sethi, G.; Kumar, A.P.; Kunnumakkara, A.B. Targeting Nuclear Receptors in Lung Cancer-Novel Therapeutic Prospects. Pharmaceuticals 2022, 15, 624. [Google Scholar] [CrossRef]
  72. Jeong, Y.; Xie, Y.; Xiao, G.; Behrens, C.; Girard, L.; Wistuba, I.I.; Minna, J.D.; Mangelsdorf, D.J. Nuclear receptor expression defines a set of prognostic biomarkers for lung cancer. PLoS Med. 2010, 7, e1000378. [Google Scholar] [CrossRef] [PubMed]
  73. More, E.; Fellner, T.; Doppelmayr, H.; Hauser-Kronberger, C.; Dandachi, N.; Obrist, P.; Sandhofer, F.; Paulweber, B. Activation of the MAP kinase pathway induces chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) expression in human breast cancer cell lines. J. Endocrinol. 2003, 176, 83–94. [Google Scholar] [CrossRef]
  74. Metivier, R.; Gay, F.A.; Hubner, M.R.; Flouriot, G.; Salbert, G.; Gannon, F.; Kah, O.; Pakdel, F. Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK. EMBO J. 2002, 21, 3443–3453. [Google Scholar] [CrossRef]
  75. Kaiser, U.; Hofmann, J.; Schilli, M.; Wegmann, B.; Klotz, U.; Wedel, S.; Virmani, A.K.; Wollmer, E.; Branscheid, D.; Gazdar, A.F.; et al. Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer. Int. J. Cancer 1996, 67, 357–364. [Google Scholar] [CrossRef]
  76. Canver, C.C.; Memoli, V.A.; Vanderveer, P.L.; Dingivan, C.A.; Mentzer, R.M., Jr. Sex hormone receptors in non-small-cell lung cancer in human beings. J. Thorac. Cardiovasc. Surg. 1994, 108, 153–157. [Google Scholar] [CrossRef] [PubMed]
  77. Yang, M.H. Estrogen receptor in female lung carcinoma. Zhonghua Jie He He Hu Xi Za Zhi 1992, 15, 138–140+189. [Google Scholar]
  78. Chen, X.Q.; Zheng, L.X.; Li, Z.Y.; Lin, T.Y. Clinicopathological significance of oestrogen receptor expression in non-small cell lung cancer. J. Int. Med. Res. 2017, 45, 51–58. [Google Scholar] [CrossRef]
  79. Huang, Q.; Zhang, Z.; Liao, Y.; Liu, C.; Fan, S.; Wei, X.; Ai, B.; Xiong, J. 17beta-estradiol upregulates IL6 expression through the ERbeta pathway to promote lung adenocarcinoma progression. J. Exp. Clin. Cancer Res. 2018, 37, 133. [Google Scholar] [CrossRef] [PubMed]
  80. Tsai, S.Y.; Carlstedt-Duke, J.; Weigel, N.L.; Dahlman, K.; Gustafsson, J.A.; Tsai, M.J.; O’Malley, B.W. Molecular interactions of steroid hormone receptor with its enhancer element: Evidence for receptor dimer formation. Cell 1988, 55, 361–369. [Google Scholar] [CrossRef]
  81. Sanchez Calle, A.; Yamamoto, T.; Kawamura, Y.; Hironaka-Mitsuhashi, A.; Ono, M.; Tsuda, H.; Shimomura, A.; Tamura, K.; Takeshita, F.; Ochiya, T.; et al. Long non-coding NR2F1-AS1 is associated with tumor recurrence in estrogen receptor-positive breast cancers. Mol. Oncol. 2020, 14, 2271–2287. [Google Scholar] [CrossRef] [PubMed]
  82. Wetendorf, M.; DeMayo, F.J. Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus. Int. J. Dev. Biol. 2014, 58, 95–106. [Google Scholar] [CrossRef] [PubMed]
  83. Stabile, L.P.; Dacic, S.; Land, S.R.; Lenzner, D.E.; Dhir, R.; Acquafondata, M.; Landreneau, R.J.; Grandis, J.R.; Siegfried, J.M. Combined analysis of estrogen receptor beta-1 and progesterone receptor expression identifies lung cancer patients with poor outcome. Clin. Cancer Res. 2011, 17, 154–164. [Google Scholar] [CrossRef]
  84. Mattern, J.; Klinga, K.; Runnebaum, B.; Volm, M. Influence of hormone therapy on human lung tumors transplanted into nude mice. Oncology 1985, 42, 388–390. [Google Scholar] [CrossRef]
  85. Laursen, K.B.; Mongan, N.P.; Zhuang, Y.; Ng, M.M.; Benoit, Y.D.; Gudas, L.J. Polycomb recruitment attenuates retinoic acid-induced transcription of the bivalent NR2F1 gene. Nucleic Acids Res. 2013, 41, 6430–6443. [Google Scholar] [CrossRef]
  86. Lin, B.; Chen, G.Q.; Xiao, D.; Kolluri, S.K.; Cao, X.; Su, H.; Zhang, X.K. Orphan receptor COUP-TF is required for induction of retinoic acid receptor beta, growth inhibition, and apoptosis by retinoic acid in cancer cells. Mol. Cell Biol. 2000, 20, 957–970. [Google Scholar] [CrossRef]
  87. Bushue, N.; Wan, Y.J. Retinoid pathway and cancer therapeutics. Adv. Drug Deliv. Rev. 2010, 62, 1285–1298. [Google Scholar] [CrossRef]
  88. Tang, X.H.; Gudas, L.J. Retinoids, retinoic acid receptors, and cancer. Annu. Rev. Pathol. 2011, 6, 345–364. [Google Scholar] [CrossRef]
  89. Gebert, J.F.; Moghal, N.; Frangioni, J.V.; Sugarbaker, D.J.; Neel, B.G. High frequency of retinoic acid receptor beta abnormalities in human lung cancer. Oncogene 1991, 6, 1859–1868. [Google Scholar]
  90. Houle, B.; Rochette-Egly, C.; Bradley, W.E. Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells. Proc. Natl. Acad. Sci. USA 1993, 90, 985–989. [Google Scholar] [CrossRef] [PubMed]
  91. Xu, X.C.; Sozzi, G.; Lee, J.S.; Lee, J.J.; Pastorino, U.; Pilotti, S.; Kurie, J.M.; Hong, W.K.; Lotan, R. Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: Implications for lung cancer development. J. Natl. Cancer Inst. 1997, 89, 624–629. [Google Scholar] [CrossRef] [PubMed]
  92. Chang, Y.S.; Chung, J.H.; Shin, D.H.; Chung, K.Y.; Kim, Y.S.; Chang, J.; Kim, S.K.; Kim, S.K. Retinoic acid receptor-beta expression in stage I non-small cell lung cancer and adjacent normal appearing bronchial epithelium. Yonsei Med. J. 2004, 45, 435–442. [Google Scholar] [CrossRef]
  93. Germain, P.; Chambon, P.; Eichele, G.; Evans, R.M.; Lazar, M.A.; Leid, M.; De Lera, A.R.; Lotan, R.; Mangelsdorf, D.J.; Gronemeyer, H. International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev. 2006, 58, 760–772. [Google Scholar] [CrossRef]
  94. Mangelsdorf, D.J.; Evans, R.M. The RXR heterodimers and orphan receptors. Cell 1995, 83, 841–850. [Google Scholar] [CrossRef]
  95. Kuznetsova, E.S.; Zinovieva, O.L.; Oparina, N.Y.; Prokofjeva, M.M.; Spirin, P.V.; Favorskaya, I.A.; Zborovskaya, I.B.; Lisitsyn, N.A.; Prassolov, V.S.; Mashkova, T.D. Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer. Mol. Biol. 2016, 50, 255–265. [Google Scholar] [CrossRef]
  96. Ai, X.; Mao, F.; Shen, S.; Shentu, Y.; Wang, J.; Lu, S. Bexarotene inhibits the viability of non-small cell lung cancer cells via slc10a2/PPARgamma/PTEN/mTOR signaling pathway. BMC Cancer 2018, 18, 407. [Google Scholar] [CrossRef]
  97. Okamura, M.; Kudo, H.; Wakabayashi, K.; Tanaka, T.; Nonaka, A.; Uchida, A.; Tsutsumi, S.; Sakakibara, I.; Naito, M.; Osborne, T.F.; et al. COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis. Proc. Natl. Acad. Sci. USA 2009, 106, 5819–5824. [Google Scholar] [CrossRef]
  98. Sasaki, H.; Tanahashi, M.; Yukiue, H.; Moiriyama, S.; Kobayashi, Y.; Nakashima, Y.; Kaji, M.; Kiriyama, M.; Fukai, I.; Yamakawa, Y.; et al. Decreased perioxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer. Lung Cancer 2002, 36, 71–76. [Google Scholar] [CrossRef] [PubMed]
  99. Keshamouni, V.G.; Reddy, R.C.; Arenberg, D.A.; Joel, B.; Thannickal, V.J.; Kalemkerian, G.P.; Standiford, T.J. Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 2004, 23, 100–108. [Google Scholar] [CrossRef]
  100. Sandgren, M.; Danforth, L.; Plasse, T.F.; DeLuca, H.F. 1,25-Dihydroxyvitamin D3 receptors in human carcinomas: A pilot study. Cancer Res. 1991, 51, 2021–2024. [Google Scholar]
  101. Srinivasan, M.; Parwani, A.V.; Hershberger, P.A.; Lenzner, D.E.; Weissfeld, J.L. Nuclear vitamin D receptor expression is associated with improved survival in non-small cell lung cancer. J. Steroid Biochem. Mol. Biol. 2011, 123, 30–36. [Google Scholar] [CrossRef] [PubMed]
  102. Mohamed, F.; Abdelaziz, A.O.; Kasem, A.H.; Ellethy, T.; Gayyed, M.F. Thyroid hormone receptor alpha1 acts as a new squamous cell lung cancer diagnostic marker and poor prognosis predictor. Sci. Rep. 2021, 11, 7944. [Google Scholar] [CrossRef] [PubMed]
  103. Iwasaki, Y.; Sunaga, N.; Tomizawa, Y.; Imai, H.; Iijima, H.; Yanagitani, N.; Horiguchi, K.; Yamada, M.; Mori, M. Epigenetic inactivation of the thyroid hormone receptor beta1 gene at 3p24.2 in lung cancer. Ann. Surg. Oncol. 2010, 17, 2222–2228. [Google Scholar] [CrossRef] [PubMed]
  104. Kwon, M.C.; Berns, A. Mouse models for lung cancer. Mol. Oncol. 2013, 7, 165–177. [Google Scholar] [CrossRef]
  105. Yang, Z.; Gimple, R.C.; Zhou, N.; Zhao, L.; Gustafsson, J.A.; Zhou, S. Targeting Nuclear Receptors for Cancer Therapy: Premises, Promises, and Challenges. Trends Cancer 2021, 7, 541–556. [Google Scholar] [CrossRef]
  106. Maniatis, S.; Petrescu, J.; Phatnani, H. Spatially resolved transcriptomics and its applications in cancer. Curr. Opin. Genet. Dev. 2021, 66, 70–77. [Google Scholar] [CrossRef]
  107. Zhang, Q.; Abdo, R.; Iosef, C.; Kaneko, T.; Cecchini, M.; Han, V.K.; Li, S.S. The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis. Nat. Commun. 2022, 13, 5983. [Google Scholar] [CrossRef]
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Figure 1. Roles of the NR2F family in the lung development. (a) An illustration of lung development. (b) NR2F1/2 were identified as markers of angiogenesis and lymphangiogenesis in lung. (c) Up-regulation of Nr2f1 increases the number of lung bronchial epithelial ciliated cells through cilia-related genes such as DNAI2.
Figure 1. Roles of the NR2F family in the lung development. (a) An illustration of lung development. (b) NR2F1/2 were identified as markers of angiogenesis and lymphangiogenesis in lung. (c) Up-regulation of Nr2f1 increases the number of lung bronchial epithelial ciliated cells through cilia-related genes such as DNAI2.
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Figure 2. The effect of nuclear receptors in lung cancer. These seven nuclear receptors are all associated with the NR2F family, and the nuclear receptors near the left of the figure tend to have a positive effect in lung cancer, while the nuclear receptors near the right of the figure tend to have a negative effect, and the nuclear receptors near the middle of the figure have a debatable effect.
Figure 2. The effect of nuclear receptors in lung cancer. These seven nuclear receptors are all associated with the NR2F family, and the nuclear receptors near the left of the figure tend to have a positive effect in lung cancer, while the nuclear receptors near the right of the figure tend to have a negative effect, and the nuclear receptors near the middle of the figure have a debatable effect.
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Table 1. Primary lung diseases related to the NR2F family.
Table 1. Primary lung diseases related to the NR2F family.
Disease TypeGenesFunctionsModels/Cell Lines/TissuesRelated Genes Related PathwaysReference
Non-cancerousCDHNr2f2↑May rescue lung hypoplasia and enhance lung growthNitrofen rat model of CDHFog2 and Gata4-[57]
Nr2f2↓Formation of CDHNkx3-2Cre/+; Nr2f2flox/flox mouse modelFog2-[21]
NR2F2↓Formation of CDH15q deletion patients specimensCHD2, RGMA and SIAT8B-[43]
IPFNr2f2↑Decreases fibrosisBleomycin-treated mice modelFn1 and Col1a1-[44]
LAMNR2F2↑Drives LAM pathogenesisS-LAM patients specimensMCTP2 and SPATA8-[46]
CancerousNSCLCNR2F1-AS1↓Decrease NSCLC cell proliferation, migration, and invasion and promoted tumor cell apoptosisNSCLC patients specimens; BEAS-2B, H522, H460, H1299, A549 and SK-MES-1 cell lines; nude mice-NR2F1-AS1/miR-493-5p/ITGB1 pathway[58]
NSCLCNR2F1-AS1↑Tumorigenic, promotes glycolysis and glutamine metabolismNSCLC patients’ specimens; 16HBE, A549 and H522 cells-miR-363–3p/SOX4 axis[59]
LUADNR2F6↑Promote proliferation, migration, invasion and enhances cell apoptosisLung adenocarcinoma patients specimens; A549, HCC827, HBE cellsmiR-142-3p-[54]
Lung CarcinomaNR2F2↑Promote cell invasionA549, HeLa, NCI-H460, H661, H520, H441, MDAMB231 and H460SMcellsFAK(PTK2), MMP2, uPA and uPAR-[52]
LUADNR2F1↑Promote growth, migration, invasion, and tumorigenicity of lung adenocarcinoma cells393P, 344SQ, 412P, 307P, 344LN, 344P, 393LN, 531LN1, 531LN2, 531LN3, 531P1, 531P2, 713P, A549 and HCC827 cellsZEB1ZEB1/NR2F1/NR2F1-AS1 axis[51]
LUADNR2F2↑Induces platinum chemotherapeutic resistance in lung cancer brain metastasisPC9, PC9-BrM1 and PC9-BrM3 cells; Nude miceGSTM1 and GPX4Wnt signaling pathway[53]
↑, upregulation; ↓, downregulation.
Table 2. Metastatic lung cancer related to the NR2F family.
Table 2. Metastatic lung cancer related to the NR2F family.
Primary Cancer TypesGenesInhibition/Promotion MetastasisModels/Cell Lines/TissuesRelated GenesRelated PathwaysReference
Breast cancerNR2F1-AS1↑InhibitionBALB/c nude mice and NOD/SCID mice; CA1h-P1, CA1h-P2 and 4175-LM2 cellsPTBP and miR-205NR2F1/ΔNp63 axis[66]
Pancreatic cancerNR2F1-AS1↑Promotion PC and matched paracancerous tissue samples; BxPC-3, Capan-2, CFPAC-1, SW1990, MIA PaCa-2, PANC-1 and HPDE cells; nude mouse NR2F1HIF pathway, AKT/mTOR pathway [69]
SACCNR2F1↑InhibitionSACC patients specimens; SACC-83 and SACC-LM cells; nude mice-CXCL12/ CXCR4 pathway[67]
HNSCCNR2F1↑InhibitionT-HEp3 cells and D-HEp3 cells; chicken chorioallantoic membrane (CAM) model; NU/J female mice model-TGF-β/SMAD4 signaling pathway[65]
Gastric cancerNr2f2↓InhibitionGastric cancer patients specimens; SGC-7901, BGC-823, MGC-803, MKN-45, MKN-28 and AGS cell lines; nude mice Fbxo21 and Zeb1Nr2f2/Snail pathway[68]
Breast carcinomaNr2f2↓InhibitionROSA26CRE-ERT2/+; Nr2f2flox/floxmouse model and PyMT+/−/ROSA26CRE-ERT2/+; Nr2f2flox/flox mouse model; B16F10 and LLC cellsAng-1VEGF signaling pathway[24]
↑, upregulation; ↓, downregulation.
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Yang, J.; Sun, W.; Cui, G. Roles of the NR2F Family in the Development, Disease, and Cancer of the Lung. J. Dev. Biol. 2024, 12, 24. https://doi.org/10.3390/jdb12030024

AMA Style

Yang J, Sun W, Cui G. Roles of the NR2F Family in the Development, Disease, and Cancer of the Lung. Journal of Developmental Biology. 2024; 12(3):24. https://doi.org/10.3390/jdb12030024

Chicago/Turabian Style

Yang, Jiaxin, Wenjing Sun, and Guizhong Cui. 2024. "Roles of the NR2F Family in the Development, Disease, and Cancer of the Lung" Journal of Developmental Biology 12, no. 3: 24. https://doi.org/10.3390/jdb12030024

APA Style

Yang, J., Sun, W., & Cui, G. (2024). Roles of the NR2F Family in the Development, Disease, and Cancer of the Lung. Journal of Developmental Biology, 12(3), 24. https://doi.org/10.3390/jdb12030024

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