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The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 8914

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Special Issue Editors

Prof. Dr. Ru Chih C. Huang

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Guest Editor

1. Department of Biology, Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218-2685, USA
2. Fellow, National Academy of Inventors, Tampa, FL 33612, USA
3. Academician, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan
Interests: chromatin structure and function; tetra-O-methyl nordihydroguaiaretic acid (M4N, terameprocol); oncogenic development in humans; chemotherapeutic drug treatments; viral replication; gene functions
Special Issues, Collections and Topics in MDPI journals

Dr. Kotohiko Kimura

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Co-Guest Editor

Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218-2685, USA
Interests: anticancer drug; combination drug treatment; transcription factor; gene regulation; alternative splicing; cancer metabolism; mitochondria; apoptosis and hypoxia

Special Issue Information

Dear Colleagues,

Recent progress in systems biology has shown that several specific factors are participants of a network that function as master regulators of cancer. These factors are usually transcription factors, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) in control of the expression of various genes which play important roles in the regulation of cancer development. This suggests that there may be a way to induce unfavorable effects on cancer development and progression by modulating the activity and/or expression of these specific factors. In this Special Issue, we will focus on studies that investigate the roles and mechanisms of transcription factors, miRNAs, and lncRNAs in the regulation of the expression of cancer-related genes and/or proteins, and explore the search for potential drugs that cause adverse effects on cancer by modulating the activity of these specific factors and thus manipulating the activity and/or expression of various cancer-related genes and/or proteins. In other words, this Special Issue is about the effort to discover potentially effective anticancer drugs by targeting transcription factors, miRNAs, and lncRNAs which function as master regulators of cancer.

Prof. Dr. Ru Chih C. Huang
Dr. Kotohiko Kimura
Guest Editors

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Keywords

transcription factors
microRNAs (miRNAs)
long non-coding RNAs (lncRNAs)
anticancer drugs
cancer
coactivators

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Published Papers (9 papers)

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Research

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22 pages, 9957 KiB

Open AccessArticle

Loss of CCL28 and CXCL17 Expression and Increase in CCR1 Expression May Be Related to Malignant Transformation of LGBLEL into Lymphoma

by Rui Liu, Mingshen Ma, Jing Li, Fuxiao Luan, Tingting Ren, Nan Wang and Jianmin Ma

Curr. Issues Mol. Biol. 2024, 46(10), 10969-10990; https://doi.org/10.3390/cimb46100652 - 29 Sep 2024

Viewed by 638

Abstract

Abstract: To investigate the differential expression of the chemokine signaling pathway in lacrimal gland benign lymphoepithelial lesion (LGBLEL) and lacrimal lymphoma, providing insights into the mechanisms underlying malignant transformation and aiding clinical differentiation. Transcriptome analysis was conducted on patients with LGBLEL, lymphoma, and orbital cavernous hemangioma (CH). Three cases of LGBLEL and three cases of lymphoma were randomly selected as control and experimental groups, respectively. A real-time quantitative polymerase chain reaction (RT-qPCR) was used to validate genes associated with the chemokine signaling pathway. Immunohistochemical (IHC) staining and quantitative Western blotting (WB) were performed for precise protein quantification. Transcriptome analysis revealed differential expression of the chemokine signaling pathway between the LGBLEL and lymphoma groups, identifying ten differentially expressed genes: CCL17, VAV2, CXCR5, NRAS, HCK, RASGRP2, PREX1, GNB5, ADRBK2, and CCL22. RT-qPCR showed that, compared to the lymphoma group, the LGBLEL group had significantly higher expression of CCL28, CXCL17, HCK, GNB5, NRAS, and VAV2 (p = 0.001, <0.001, <0.001, <0.001, =0.020, <0.001, respectively) and lower expression of CCR1 (p = 0.002). IHC staining and quantitative analysis confirmed significant differences in protein expression between the groups for CCL28, CCR1, CXCL17, HCK, GNB5, NRAS, and VAV2 (p = 0.003, 0.011, 0.001, 0.024, 0.005, 0.019, and 0.031, respectively). While IHC provided localization, WB offered greater precision. WB revealed that, compared to the lymphoma group, the LGBLEL group exhibited significantly higher expression of CCL28, CXCL17, HCK, GNB5, NRAS, and VAV2 (p = 0.012, 0.005, 0.009, 0.011, 0.008, and 0.003, respectively) and lower expression of CCR1 (p = 0.014). The chemokine signaling pathway plays a role in the malignant transformation of LGBLEL. The decreased expression of CCL28 and CXCL17, coupled with the increased expression of CCR1, may be linked to the progression of LGBLEL into lymphoma. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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20 pages, 7362 KiB

Open AccessArticle

Improvement of Docetaxel Efficacy through Simultaneous Blockade of Transcription Factors NF-κB and STAT-3 Using Pentoxifylline and Stattic in Prostate Cancer Cells

by José Roberto Cruz-Lozano, Georgina Hernández-Flores, Pablo Cesar Ortiz-Lazareno, Luis Arturo Palafox-Mariscal, Katia Carolina Vázquez-Ibarra, Karen Lilith González-Martínez, María Martha Villaseñor-García and Alejandro Bravo-Cuellar

Curr. Issues Mol. Biol. 2024, 46(9), 10140-10159; https://doi.org/10.3390/cimb46090605 - 14 Sep 2024

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Abstract

Prostate cancer (PCa) is a common and deadly disease in men. It is often diagnosed at advanced stages, at which point patients are treated mainly with docetaxel (DTX), which is effective but limited by resistance and side effects. Overactivation of the transcription factors NF-κB and STAT-3 plays a critical role in the development, progression, and chemoresistance of PCa. In this regard, the blockade of NF-κB with pentoxifylline (PTX) or STAT-3 with Stattic (STT) is known to increase the sensitivity of tumor cells to chemotherapy in both in vitro and in vivo models. We investigated whether simultaneous blockade with PTX and STT increases the efficacy of the DTX treatment in inducing apoptosis in metastatic castration-resistant PCa DU-145 cells. Our results showed that the combination of PTX + STT led to higher levels of apoptosis, regardless of whether or not DTX was present in the treatment. Determining caspases and ΔΨm indicates that the intrinsic caspase pathway of apoptosis is principally favored. In addition, this combination inhibited proliferation and colony formation and arrested the cell cycle in the G1 phase. These results indicate that the combination of the PTX + STAT-3 inhibitor could potentiate DTX effectively, opening the possibility of effective treatments in PCa. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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24 pages, 2833 KiB

Open AccessArticle

Dysregulation of Transposon Transcription Profiles in Cancer Cells Resembles That of Embryonic Stem Cells

by Anna I. Solovyeva, Roman V. Afanasev, Marina A. Popova and Natella I. Enukashvily

Curr. Issues Mol. Biol. 2024, 46(8), 8576-8599; https://doi.org/10.3390/cimb46080505 - 5 Aug 2024

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Abstract

Transposable elements (TEs) comprise a substantial portion of the mammalian genome, with potential implications for both embryonic development and cancer. This study aimed to characterize the expression profiles of TEs in embryonic stem cells (ESCs), cancer cell lines, tumor tissues, and the tumor microenvironment (TME). We observed similarities in TE expression profiles between cancer cells and ESCs, suggesting potential parallels in regulatory mechanisms. Notably, four TE RNAs (HERVH, LTR7, HERV-Fc1, HERV-Fc2) exhibited significant downregulation across cancer cell lines and tumor tissues compared to ESCs, highlighting potential roles in pluripotency regulation. The strong up-regulation of the latter two TEs (HERV-Fc1, HERV-Fc2) in ESCs has not been previously demonstrated and may be a first indication of their role in the regulation of pluripotency. Conversely, tandemly repeated sequences (MSR1, CER, ALR) showed up-regulation in cancer contexts. Moreover, a difference in TE expression was observed between the TME and the tumor bulk transcriptome, with distinct dysregulated TE profiles. Some TME-specific TEs were absent in normal tissues, predominantly belonging to LTR and L1 retrotransposon families. These findings not only shed light on the regulatory roles of TEs in both embryonic development and cancer but also suggest novel targets for anti-cancer therapy. Understanding the interplay between cancer cells and the TME at the TE level may pave the way for further research into therapeutic interventions. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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20 pages, 1449 KiB

Open AccessArticle

Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer

by Lincoln Sutherland, Jacob Lang, Norberto Gonzalez-Juarbe and Brett E. Pickett

Curr. Issues Mol. Biol. 2024, 46(7), 7114-7133; https://doi.org/10.3390/cimb46070424 - 6 Jul 2024

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Abstract

Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two significant differentially expressed genes (DEGs) between these patient cohorts, with “PLK1 signaling events” being the most significant signaling pathway. We also identified PRDX4 and E2F8 gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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21 pages, 5275 KiB

Open AccessArticle

Expression and Functional Analysis of Immuno-Micro-RNAs mir-146a and mir-326 in Colorectal Cancer

by Ovidiu Farc, Liviuta Budisan, Florin Zaharie, Roman Țăulean, Dan Vălean, Elena Talvan, Ioana Berindan Neagoe, Oana Zănoagă, Cornelia Braicu and Victor Cristea

Curr. Issues Mol. Biol. 2024, 46(7), 7065-7085; https://doi.org/10.3390/cimb46070421 - 5 Jul 2024

Cited by 1 | Viewed by 1038

Abstract

Micro-RNAs (miRNAs) are non-coding RNAs with importance in the development of cancer. They are involved in both tumor development and immune processes in tumors. The present study aims to characterize the behavior of two miRNAs, the proinflammatory miR-326-5p and the anti-inflammatory miR-146a-5p, in colorectal cancer (CRC), to decipher the mechanisms that regulate their expression, and to study potential applications. Tissue levels of miR-326-5p and miR-146a-5p were determined by qrt-PCR (real-time quantitative reverse transcription polymerase chain reaction) in 45 patients with colorectal cancer in tumoral and normal adjacent tissue. Subsequent bioinformatic analysis was performed to characterize the transcriptional networks that control the expression of the two miRNAs. The biomarker potential of miRNAs was assessed. The expression of miR-325-5p and miR-146a-5p was decreased in tumors compared to normal tissue. The two miRNAs are regulated through a transcriptional network, which originates in the inflammatory and proliferative pathways and regulates a set of cellular functions related to immunity, proliferation, and differentiation. The miRNAs coordinate distinct modules in the network. There is good biomarker potential of miR-326 with an AUC (Area under the curve) of 0.827, 0.911 sensitivity (Sn), and 0.689 specificity (Sp), and of the combination miR-326-miR-146a, with an AUC of 0.845, Sn of 0.75, and Sp of 0.89. The miRNAs are downregulated in the tumor tissue. They are regulated by a transcriptional network in which they coordinate distinct modules. The structure of the network highlights possible therapeutic approaches. MiR-326 and the combination of the two miRNAs may serve as biomarkers in CRC. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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Review

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35 pages, 3888 KiB

Open AccessReview

Gene Expression Regulation and the Signal Transduction of Programmed Cell Death

by Saqirile, Yuxin Deng, Kexin Li, Wenxin Yan, Ke Li and Changshan Wang

Curr. Issues Mol. Biol. 2024, 46(9), 10264-10298; https://doi.org/10.3390/cimb46090612 - 16 Sep 2024

Viewed by 834

Abstract

Cell death is of great significance in maintaining tissue homeostasis and bodily functions. With considerable research coming to the fore, it has been found that programmed cell death presents in multiple modalities in the body, which is not only limited to apoptosis, but also can be divided into autophagy, pyroptosis, ferroptosis, mitotic catastrophe, entosis, netosis, and other ways. Different forms of programmed cell death have disparate or analogous characteristics with each other, and their occurrence is accompanied by multiple signal transduction and the role of a myriad of regulatory factors. In recent years, scholars across the world have carried out considerable in-depth research on programmed cell death, and new forms of cell death are being discovered continually. Concomitantly, the mechanisms of intricate signaling pathways and regulators have been discovered. More critically, cancer cells tend to choose distinct ways to evade cell death, and different tumors adapt to different manners of death. Therefore, targeting the cell death network has been regarded as an effective tumor treatment strategy for a long time. The objective of our paper is to review the signaling pathways and gene regulation in several typical types of programmed cell death and their correlation with cancer. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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17 pages, 891 KiB

Open AccessReview

MicroRNAs Associated with IgLON Cell Adhesion Molecule Expression

by Marco Salluzzo, Clara Vianello, Francesca Flotta, Roberto Rimondini and Lucia Carboni

Curr. Issues Mol. Biol. 2024, 46(7), 7702-7718; https://doi.org/10.3390/cimb46070456 - 19 Jul 2024

Viewed by 1061

Abstract

The IgLON family of cell adhesion molecules consists of five members (LSAMP, OPCML, neurotrimin, NEGR1, and IgLON5) discovered as supporters of neuronal development, axon growth and guidance, and synapse formation and maintenance. Tumour suppression properties have recently been emerging based on antiproliferative effects through the modulation of oncogenic pathways. Available evidence endorses a role for non-coding RNAs or microRNAs as relevant controllers of IgLON molecule expression that can impact their critical physiological and pathological roles. Current findings support a function for long non-coding RNAs and microRNAs in the modulation of LSAMP expression in cell senescence, cancer biogenesis, addiction, and pulmonary hypertension. For OPCML, data point to a role for several microRNAs in the control of tumorigenesis. MicroRNAs were detected in neurotrimin-mediated functions in cancer biogenesis and in Schwann cell responses to peripheral nerve injury. For NEGR1, studies have mainly investigated microRNA involvement in neuronal responses to ischaemic injury, although data also exist about tumorigenesis and endothelial cell dysfunction. For IgLON5, information is only available about microRNA involved in myocardial infarction. In conclusion, despite much information being still missing and further research needed, the emerging picture favours a model in which non-coding RNAs exert a crucial role in modulating IgLON expression, ultimately affecting their important physiological functions. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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11 pages, 1098 KiB

Open AccessReview

Mechanism of DAPK1 for Regulating Cancer Stem Cells in Thyroid Cancer

by Mi-Hyeon You

Curr. Issues Mol. Biol. 2024, 46(7), 7086-7096; https://doi.org/10.3390/cimb46070422 - 5 Jul 2024

Viewed by 958

Abstract

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca²⁺/CaM)-dependent serine/threonine (Ser/Thr) protein kinase and is characteristically downregulated in metastatic cancer. Several studies showed that DAPK1 is involved in both the early and late stages of cancer. DAPK1 downregulation is elaborately controlled by epigenetic, transcriptional, posttranscriptional, and posttranslational processes. DAPK1 is known to regulate not only cancer cells but also stromal cells. Recent studies showed that DAPK1 was involved not only in tumor suppression but also in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in colon and thyroid cancers. CSCs are major factors in determining cancer aggressiveness in cancer metastasis and treatment prognosis by influencing EMT. However, the molecular mechanism involved in the regulation of cancer cells by DAPK1 remains unclear. In particular, little is known about the existence of CSCs and how they are regulated in papillary thyroid carcinoma (PTC) among thyroid cancers. In this review, we describe the molecular mechanism of CSC regulation by DAPK1 in PTC progression. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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Other

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14 pages, 8675 KiB

Open AccessBrief Report

TLR4 Downregulation Identifies High-Risk HPV Infection and Integration in H-SIL and Squamous Cell Carcinomas of the Uterine Cervix

by Angela Santoro, Giuseppe Angelico, Damiano Arciuolo, Giulia Scaglione, Belen Padial Urtueta, Gabriella Aquino, Noemy Starita, Maria Lina Tornesello, Rosalia Anna Rega, Maria Carmela Pedicillo, Manuel Mazzucchelli, Ilenia Sara De Stefano, Rosanna Zamparese, Giuseppina Campisi, Giorgio Mori, Gian Franco Zannoni and Giuseppe Pannone

Curr. Issues Mol. Biol. 2024, 46(10), 11282-11295; https://doi.org/10.3390/cimb46100670 - 10 Oct 2024

Viewed by 787

Abstract

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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