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LABORATORIO CLÍNICO Discussion The association between miRNA SNPs and HCC - W. Li et al Morbidity and mortality of liver tumors are extremely high and increasing rapidly. Therefore, early diagnosis and intervention in cancer are very crucial and urgent. Epidemiological investigations show that the prevalence of HCC varies in different geographical regions, with relatively higher incidence 514 in many Asian countries and Sub-Saharan Africa, especially in China, where almost half of the worldwide cases and deaths occur. Major risk factors associated with HCC include chronic HBV or HCV infection, excessive alcohol intake, alcoholic and nonalcoholic steatohepatitis, exposure to Aspergillus flavus toxin B, disorders of the immune system, etc9. Eighty percent of HCC patients in China have HBV infection, while only a small part of the population infected with HBV will progress into HCC. Meanwhile, research also shows that individual genetic factors contribute improtantly to hepatocarcinogenesis10. For instance, it has been certified that polymorphisms of cytochrome P450 2E1 (CYP2E1) plays a crucial role in cigarette smoking-related hepatocarcinogenesis, which is of great importance in the metabolism of many carcinogens. MicroRNAs (miRNAs), a group of small noncoding RNAs of about 22 nucleotides, play a significant role in the regulation of gene expression. Mature miRNAs, originating from long pri-miRNAs and pre-miRNAs, complementarily bind to the 3’untranslated regions (UTRs) of target mRNAs, and control many biological pathways such as cell growth, differentiation, metabolism and apoptosis11,12. Alteration of miRNA expression is observed in the formation and development of human diseases, disturbing the expression, maturation and target recognition of miRNAs, consequently alters protein expression and leads to phenotypic differences, contributing to the different risks of human diseases, including malignant tumors like HCC 13-15. Therefore, SNPs in miRNAs are critical genetic factors in the initiation and progression of tumors. miRNA3152 has been studied in a previous research enrolling 53 PDAC patients vs 30 pancreatitis and 13 healthy control, validating that miRNA3152 is upregulated in PDAC 16. But it has not mentioned any SNP. To the best of our knowledge, in our 498 vs 520 case-control study, we have firstly revealed that the genotype of AA or A allele of rs13299349 in miRNA3152 significantly associated with the susceptibility of HCC, indicating rs13299349is a risky factor to HCC. Another important result is that rs13299349 is correlated to the size and number of tumor foci. It is shown that the structure of miRNA3152 with A allele of rs13299349 has a larger reduction of free energy (ΔG = -45.6 kcal/mol) compared with G allele (ΔG = -41.7 kcal/mol) by Mfold web server, indicating the A allele may increase the stability of miRNA3152 that results in an overexpression of miRNA3152. Therefore, at the same time, our study got a consistent result with the PDAC, suggesting that rs13299349 in miRNA3152 might be an advantageous element to the cancers. In addition, our study indicates that miRNA449 might act as a tumor suppressor. It has been verified that miR-449 is down-regulated or lost in gastric cells, lung adenocarcinoma cell and testicular cancer cells17-20. In addition, our research demonstrates for the first time that in miRNA449b (rs10061133), G allele is significantly associated with an increased risk of susceptibility to HCC compared with A allele. However, the genotype of GG or AG shows no statistical significance, which may be not related to susceptibility of HCC. To sum up, this study explores that rs13299349 in miRNA3152 and G allele rs10061133 in miRNA449b are significantly related to the susceptibility of HCC, which might be used in companion with other significant miRNA SNPs as a prediction tool. To further understand the results of our study and apply the basic research to clinic, more functional studies of rs13299349 and rs10061133 are required. In conclusion, this study shows an association between the miRNA SNPs and the susceptibility to hepatocellular carcinoma, hoping to reveal some roles and mechanisms of SNPs within miRNAs in the occurrence and development of primary liver cancer. We expect that our efforts and findings will facilitate the use of miRNA SNPs in early detection and confirmation of HCC, as well as an effective treatment. Acknowledgements: This work was supported by the grant from the Ministry of Science and Technology of China (No. 2012CB910104). The funder had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Rev Med Chile 2016; 144: 508-515


Abril 2016
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