Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

Abstract

BackgroundNumerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT), a known mediator of cellular immortalization.MethodsWe investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3) and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes.ResultsWe showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs) in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC.ConclusionsWe propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: Involvement of p53/FoxO3A axis

“…Leptin treatment also showed increase in MMP-9 expression in hepatic cancer cells [53] and endothelial cells [54] to induce invasion of tumor cells. Furthermore, FoxO3A activation has been also shown to cause tumor progression through induction of matrix metalloproteinase, such as MMP-9 and MMP-13 [55].…”

Vitamin D Suppresses Leptin Stimulation of Cancer Growth through microRNA

“…Although remaining to be determined, 27-hydroxycholesterol may increase telomerase activity through ERα and 1,25(OH) 2 D 3 may prevent hypercholesterolemia-associated cancer risk through miR-498. Likewise, leptin has been shown to increase telomerase activity in breast and hepatocellular carcinoma cells through STAT3 (42, 43) and c-Myc (43), which may not depend on ERα. 1,25(OH) 2 D 3 should also be able to suppress the ERα-independent leptin effect on telomerase through the same miR-498 pathway.…”

Shared Risk Factors in Cardiovascular Disease and Cancer

“…For example, leptin has been shown to be a critical regulator of hepatocellular carcinoma through its effects on telomerase reverse transciptase. 41 Leptin also plays a pivotal role in obesity-related CVD, as demonstrated by numerous clinical and animal model investigations. 42 …”