The Role Of Adipokines In Digestive System Cancer

PART 1. Study on the association of adiponectin gene variants with hepatocellular carcinoma Purpose Increasing lines of evidence have suggested that adiponectin, an adipocyte-derived hormone, plays an important role in the development of hepatocellular carcinoma (HCC). However, the relationship between genetic variants in adiponectin gene(ADIPOQ) and HCC has not been explored before. Therefore, we performed a case-control study to examine the association of haplotype tagging single nucleotide polymorphisms (SNPs) in ADIPOQ with HCC risk.Methods We genotyped 131 HCC patients and 131 non-cancer controls for five haplotype tagging single nucleotide polymorphisms (SNPs) of ADIPOQ (rs266729, rs822395, rs822396, rs2241766 and rs1501299) by using PCR amplification and direct sequencing. Logistic regression was used to estimate the risk of HCC with each individual SNP. Results Of the five tested SNPs, rs 1501299 showed a strong association with HCC risk. After adjustment for age, sex, serological status of hepatitis virus B core antibody, and other SNPs, the odds ratio (95% confidence interval) were 3.13 (1.23-8.01) and 4.53 (1.84-11.16), respectively, for genotypes GT and GG versus TT.Conclusions We reported, for the first time, an association of ADIPOQ polymorphisms with HCC risk. Our results thus implicate ADIPOQ SNP rs1501299 as a susceptibility locus for HCC.PART 2. Study on the role of leptin on the human pancreatic cancer cells and its underlying mechanisms Purpose Obesity is an independent risk factor for pancreatic cancer. The circulating level of leptin, an important adipokine, was increased in pancreatic cancer patients, suggesting a role of leptin in the development of pancreatic cancer. Leptin has been associated with several human malignancies, including hepatocellular carcinoma, breast cancer, postate cancer. However, its effects on human pancreatic cancer remain unclear. The aim of our study is to investigate the effects of leptin on the biological behavior of human pancreatic cancer cells, as well as the underlying mechanisms.Methods Reverse transcription PCR and Western blot were used to detected the expressions of Leptin and its functional receptor OB-Rb in human pancreatic cancer celis (AsPC-i, PANC-1, BxPC-3, and CFPAC-1). To investigate the effects of leptin on pancreatic cancer, these pancreatic cancer cells were treated with recombinant human leptin (100ng/ml), and subjected to the cell proliferation, migration, invasion tests. To explore the underlying mechanism, the phosphorylation of STAT3 and the expression of MMP13 were detected by using Western blot. AG490 was used to selectively inhibit activation of STAT3 in pancreatic cancer cells. Furthermore, we collected supernatant analyzed for MMP activity via gelatin zymography. In addition, leptin was overexpressed in human pancreatic cancer cells via letiviral vectors to confirm its effects and the underlying mechanism.Results All tested human pancreatic cancer cells expressed the leptin receptor OB-Rb. However, the leptin was not detected in these cells. It was shown that leptin significantly promoter the migration (P< 0.01 for AsPC-1 and P< 0.01 for PANC-1, respectively) and invasion (P< 0.05 for AsPC-1 and P< 0.01 for PANC-1, respectively) of human pancreatic cancer cells, although it has no effects on cell proliferation. We further found that leptin treatment could induce the phosphorylation of STAT3 and the expression of MMP13. Inhibiting the activity of STAT3 by AG490 significantly inhibited the leptin-induced cell migration and invasion, as well as the leptin-induced MMP13 expression The overexpression of leptin in human pancreatic cancer cells could mimic the effects of exogenous leptin treatment. However, the overexpression of MMP13 just promoted the invasion of pancreatic cancer cell, but had no effects on cell migration.Conclusions Leptin can affect the biological behavior of human pancreatic cancer cells via a paracrine or endocrine manner. It stimulated the migration and invation of pancreatic cells through a STAT3-dependent signaling pathway. In addition, MMP13 plays a critical role in leptin-induced cell invasion.