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4 pages, 203 KiB

Open AccessEditorial

Leptin and Beyond: Actors in Cancer

by Ines Barone and Cinzia Giordano

Biomolecules 2021, 11(12), 1836; https://doi.org/10.3390/biom11121836 - 6 Dec 2021

Cited by 3 | Viewed by 2545

Abstract

Leptin is a 16-kDa multifunctional, neuroendocrine peptide hormone secreted by adipocytes in proportion to total adipose tissue mass, known to control food intake, energy homeostasis, immune response, and reproductive processes [...] Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

Research

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13 pages, 3295 KiB

Open AccessArticle

Leptin Is Associated with Poor Clinical Outcomes and Promotes Clear Cell Renal Cell Carcinoma Progression

by Wen-Lang Fan, Yuan-Ming Yeh, Tsung-Ta Liu, Wei-Ming Lin, Tse-Yen Yang, Chao-Wei Lee and Tsung-Chieh Lin

Biomolecules 2021, 11(3), 431; https://doi.org/10.3390/biom11030431 - 15 Mar 2021

Cited by 10 | Viewed by 2835

Abstract

Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients’ clinical information have revealed leptin’s prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC [...] Read more.

Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients’ clinical information have revealed leptin’s prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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18 pages, 2333 KiB

Open AccessFeature PaperArticle

Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

by Salvatore Panza, Umberto Russo, Francesca Giordano, Antonella Leggio, Ines Barone, Daniela Bonofiglio, Luca Gelsomino, Rocco Malivindi, Francesca Luisa Conforti, Giuseppina Daniela Naimo, Cinzia Giordano, Stefania Catalano and Sebastiano Andò

Biomolecules 2020, 10(6), 886; https://doi.org/10.3390/biom10060886 - 9 Jun 2020

Cited by 18 | Viewed by 3959

Abstract

Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor [...] Read more.

Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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20 pages, 2245 KiB

Open AccessFeature PaperArticle

Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages

by Luca Gelsomino, Cinzia Giordano, Giusi La Camera, Diego Sisci, Stefania Marsico, Antonella Campana, Roberta Tarallo, Antonio Rinaldi, Suzanne Fuqua, Antonella Leggio, Fedora Grande, Daniela Bonofiglio, Sebastiano Andò, Ines Barone and Stefania Catalano

Biomolecules 2020, 10(4), 543; https://doi.org/10.3390/biom10040543 - 3 Apr 2020

Cited by 35 | Viewed by 4200

Abstract

Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using [...] Read more.

Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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7 pages, 905 KiB

Open AccessCommunication

Leptin-Responsive MiR-4443 Is a Small Regulatory RNA Independent of the Canonic MicroRNA Biogenesis Pathway

by Ari Meerson

Biomolecules 2020, 10(2), 293; https://doi.org/10.3390/biom10020293 - 13 Feb 2020

Cited by 8 | Viewed by 3027

Abstract

The human small RNA miR-4443 is functionally involved in several types of cancer and in the biology of the immune system, downstream of insulin and leptin signaling. Next generation sequencing evidence and structural prediction suggest that miR-4443 is not produced via the canonical [...] Read more.

The human small RNA miR-4443 is functionally involved in several types of cancer and in the biology of the immune system, downstream of insulin and leptin signaling. Next generation sequencing evidence and structural prediction suggest that miR-4443 is not produced via the canonical Drosha–Exportin 5–Dicer pathway of microRNA biogenesis. We tested this hypothesis by using qRT-PCR to measure miR-4443 and other microRNA levels in HCT-116 cells with Drosha, Exportin 5, and Dicer knockouts, as well as in the parental cell line. Neither of the knockouts decreased miR-4443 levels, while the levels of canonical microRNAs (miR-21 and let-7f-5p) were dramatically reduced. Previously published Ago2-RIP-Seq data suggest a limited incorporation of miR-4443 into RISC, in agreement with the functional studies. The miR-4443 locus shows conservation in primates but not in other mammals, while its seed region appears in additional microRNAs. Our results suggest that miR-4443 is a Drosha, Exportin 5, and Dicer-independent, non-canonical small RNA produced by a yet unknown biogenesis pathway. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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Review

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18 pages, 14341 KiB

Open AccessReview

Leptin-Activity Modulators and Their Potential Pharmaceutical Applications

by Marianna Greco, Marzia De Santo, Alessandra Comandè, Emilia Lucia Belsito, Sebastiano Andò, Angelo Liguori and Antonella Leggio

Biomolecules 2021, 11(7), 1045; https://doi.org/10.3390/biom11071045 - 16 Jul 2021

Cited by 29 | Viewed by 5906

Abstract

Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In [...] Read more.

Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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16 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Leptin, Both Bad and Good Actor in Cancer

by Carlos Jiménez-Cortegana, Ana López-Saavedra, Flora Sánchez-Jiménez, Antonio Pérez-Pérez, Jesús Castiñeiras, Juan A. Virizuela-Echaburu, Luis de la de la Cruz-Merino and Víctor Sánchez-Margalet

Biomolecules 2021, 11(6), 913; https://doi.org/10.3390/biom11060913 - 20 Jun 2021

Cited by 37 | Viewed by 6374

Abstract

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the [...] Read more.

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the “obesity paradox”, and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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29 pages, 3378 KiB

Open AccessReview

New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

by Monserrat Olea-Flores, Juan C. Juárez-Cruz, Miriam D. Zuñiga-Eulogio, Erika Acosta, Eduardo García-Rodríguez, Ana E. Zacapala-Gomez, Miguel A. Mendoza-Catalán, Julio Ortiz-Ortiz, Carlos Ortuño-Pineda and Napoleón Navarro-Tito

Biomolecules 2020, 10(12), 1676; https://doi.org/10.3390/biom10121676 - 15 Dec 2020

Cited by 28 | Viewed by 5789

Abstract

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal [...] Read more.

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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