Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3'UTR is associated with fluorouracil resistance of hepatocellular carcinoma

Jin Ma, Rui Guo, Ting Wang, Xia Pan, Xiaoyong Lei
Molecular Medicine Reports 2015, 11 (1): 677-81
B-cell lymphoma-extra large (Bcl-xl) is an anti-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family that is often found to be overexpressed in human hepatocellular carcinoma (HCC), therefore conferring a survival advantage to tumor cells. microRNA (miRNA) let-7b is downregulated in HCC and its expression correlates with multidrug resistance. Using computational programs, it was predicted that the 3' untranslated region (UTR) of the Bcl-xl gene contains a potential miRNA binding site for let-7b, and that a single nucleotide polymorphism (SNP) site rs3208684 (A or C allele) resides within this binding site. Luciferase assays and western blot analysis demonstrated that let‑7b targeted Bcl-xl gene expression and negatively regulated the amount of Bcl-xl protein. SNP rs3208684 (A>C) variation enhanced the expression of Bcl-xl by disrupting the binding of let-7b to the 3'UTR of Bcl-xl. The effects of the two polymorphic variants on chemotherapeutic drug sensitivity were determined by cell counting kit 8 assays. Overexpression of the Bcl-xl mutated (C) allele in BEL-7402 HCC cells significantly decreased fluorouracil (5-FU) sensitivity, as compared with mock transfection and overexpression of the wild-type allele. From this, it was concluded that let-7b increased 5-FU sensitivity by repressing Bcl-xl expression in HCC cells. These results suggest that SNP (rs3208684) may be a potential marker for personalized treatment.

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