Exploration on the Ralation between Genetic Polymorphisms in TGF-β Signaling Pathway and Hepatocellular Carcinoma and Nasopharyngeal Arcinoma
|School||Guangxi Medical University|
|Keywords||hepatocellular carcinoma nasopharyngeal carcinoma transforming growth factor-beta1 Monocyte chemoattractant protein-1 single nucleotide polymorphism associaton study|
Hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC) are common cancers in the world, which incidence and mortality are particularly higher in China. At present, the difficulty of early diagnosis, high rate of recurrence and metastasis, and the deficiency of directed therapy are the major problem in the treatment of the two cancers. Hence, the research on the pathogenesis of these cancers and the development of new technology on diagnosis and treatment are of great importance. The main risk factors for HCC development include chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), dietary exposure to aflatoxinB1 contaminated foodstuffs and consumption of alcohol; the main risk factors for NPC development include infection with EB virus and exposure to chemical carcinogen. The control of the risk factors may decrease the risk of tumorigenesis. HCC and NPC are multi-factorial cancers, and the notably family-clustered phenomenon in the occurrence indicates the important role of host genetic factors in the development of these cancers. The identification of susceptility genes and the elucidation of the interaction between these genes and other risk factors may provide specific genetic biomarkers and targets for early diagnosis and clinic treatment, which may also be applied in the detection of recurrence and metastasis after operation.The TGF-βs (transforming growth factor-beta1 , TGF-β)are multifunctional growth factors that signal through a well-characterized pathway of transmembrane serine-threonine kinase receptors and intracellular signaling molecules of the Smad family. Virtually every cell in the body, produces TGF-β. TGF-βsignaling regulates the proliferation and differentiation of cells, apoptosis, extracellular matrix deposition.,angiogenesis and immunologic system. More and more reports indicated that TGF-βsignaling have been linked to numerous kinds of cancer. in cancer development: suppressing the early stage tumor growth by arresting the cell cycle , inhibiting cellular proliferation and promoting apoptosis.,but promoting tumor progression and metastasis by inducing the cellular changes stimulating angiogenesis, suppressing immune system. TGFβ1, TGFβRI,TGFβRII,MCP1 are the key components in the TGF-βsignaling pathway,the variants of them would inactivate the TGF-βsignaling pathway ,and association with diverse cancer including Hepatocellular carcinoma and nasopharyngeal carcinoma. Therefore, TGFβ1, TGFβRI,TGFβRII,MCP1are considered to be excellent biologically candidate susceptibility genes.Functional polymorphisms in TGFβ1, TGFβRI, TGFβRII, MCP1gene are known to influence gene expression, protein activity, protein stability and protein-protein interactions. These polymorphisms are found to be associated with the onset and progression of common cancers. The most common polymorphism in human genome is the substitution of single nucleotide, which is described as single nucleotide polymorphisms (SNPs). We select the 7 functional SNPs : TGFβ1, TGFβRI, TGFβRII, MCP1to examined wheather they were related to the risk of hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC) in Chinese population.The polymorphsims were genotyped in 434 patients with HCC, 539 patients with NPC and 480 controls by PCR-RFLP method.The association between these polymorphisms and disease state was evaluated while controlling for confounding factors. However,we found no evidence for significant association between the TGFβ1 C-509T, TGFβRIInt7G24A, TGFβRI*6A, TGFβRIIG-875A, MCP1A-2136Tpolymorphisms and risk of HCC and NPC.When the analyses were stratified by age , sex, status of smoking and drinking , and pack-years of smoking, the association remained negative. Meanwhile, there was no association between these polymorphisms and NPC severity. our findings therefore suggest that the TGFβ1 C-509T, TGFβRIInt7G24A, TGFβRI*6A, TGFβRIIG-875A, MCP1A-2136T polymorphisms may not play a major role in mediating susceptibility to HCC and NPC. Our associaton studies have found that MCP1 A-2518G is associated with susceptibility to HCC and NPC. the MCP1 A-2518G GG genotype was associated with susceptibility to HCC(95% CI: 1.224-2.550, P = 0.002) , further analysis stratified by HBV status also showed significant association between the MCP1 A-2518G and the HCC risk(95% CI: 1.334-4.074, P = 0.003) . The G allele is related to the increased risk of NPC(95% CI: 1.085-1.833, P = 0.01), but there was no association between these polymorphisms and NPC severity.The association study results showed that promoter region functional SNP MCP1A-2518G is associated with susceptibility to HCC and NPC.