let-7b and let-7c are determinants of intrinsic chemoresistance in renal cell carcinoma

Abstract

BackgroundRenal cell carcinoma (RCC) is characterized by inherent resistance to chemotherapy. Earlier studies demonstrated that microRNAs (miRNAs) might be involved in the chemosensitivity of cancers. MicroRNA let-7, a putative tumor suppressor, is dysregulated in many cancers. Our study aims to investigate the exact role of let-7 in chemotherapy sensitivity of 5-fluorouracil (5-FU) in RCC.MethodsThe clinical significance of let-7b and let-7c expression in surgically resected specimens was assessed by qRT-PCR. Cell proliferation assay and colony formation assay were used to assess the survival of 786-O cells treated with let-7b or let-7c combined with 5-FU. Western blot was used to detect the expression of Akt2 and caspase-7. Luciferase assay was used to detect the direct binding of let-7b and let-7c to the 3′-untranslated region (UTR) of Akt2.ResultsExpression of let-7b and let-7c was significantly decreased in 32 paired clear cell renal cell carcinoma tissue specimens and the dysregulation of let-7b was associated with pathological grade. Transfection of let-7b or let-7c combined with 5-FU inhibited proliferation and potentiated the antitumor efficacies of 5-FU at tolerated concentration. let-7b and let-7c suppressed the luciferase activity of reporter plasmid containing the 3′-UTR of Akt2. Overexpression of let-7b and let-7c reduced Akt2 expression, and Akt2 inhibition enhanced the sensitivity to 5-FU by affecting apoptotic pathway.ConclusionsExpression of let-7b and let-7c was frequently decreased in clear cell renal cell carcinoma tissues. The dysregulation of let-7b and let-7c may be involved in chemoresistance of RCC cells to 5-FU by down-regulating Akt2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12957-015-0596-4) contains supplementary material, which is available to authorized users.

Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease

“…In addition, it has been reported that let-7c is significantly down-regulated in renal tumors compared to normal tissues (Peng et al 2015), while we observed a significant increase in their abundance in exosomes of CKD patients. Similarly, expression of miR-31 was reported to be down-regulated in polycystic kidney disease (Pandey et al 2008), whereas in exosomes from CKD patients we found it to be significantly increased.…”

“…For some miRNAs, e.g., let-7c, it has been shown that transfection of let-7c combined with 5-fluorouracil (5-FU) treatment in renal cell carcinoma inhibits cell proliferation and enhances the antitumor efficacy of 5-FU (Peng et al 2015). However, the function of differentially expressed urinary-derived exosomal miRNAs poses the question about their biological roles, if any.…”

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

“…In essence, over 10% of all reported research findings of miRNA influences in cancer chemoresistance demonstrated that such a phenotype modulation was effected through simultaneous dysregulation of multiple miRNAs, rather than an individual putative chemoresistance miRNA—though no specific miRNA combination was identified as most prevalent by the authors [44,46,47,48,49,62,67,71,76,81,85,88,132,133,158,168,201,203,211,212,213,217,223,224,228,230]. This suggests that miRNA influences on cellular functions also occur at a more complex level, whereby it is a signature dysregulated expression pattern of two (or more) miRNAs that trigger simultaneous downregulation of a specific set of target transcripts leading to an ultimate change in cellular/tissue phenotype.…”

MicroRNA‑138 suppresses cell proliferation and invasion of renal cell carcinoma by directly targeting SOX9

“…It is estimated that there are ~30,000 new cases and 12,000 mortalities due to RCC every year in the USA (2). RCC may be histologically classified into three subtypes, including clear cell RCC, papillary RCC and chromophobe RCC.…”