Abstract
Many studies demonstrated unique microRNA profiles in lung cancer. Nonetheless, the role and related signal pathways of miR-375 in lung cancer are largely unknown. Our study investigated relationships between carcinogenesis and miR-375 in adenocarcinoma, squamous cell carcinoma and small cell lung carcinoma to identify new molecular targets for treatment. We evaluated 723 microRNAs in microdissected cancerous cells and adjacent normal cells from 126 snap-frozen lung specimens using microarrays. We validated the expression profiles of miR-375 and its 22 putative target mRNAs in an independent cohort of 78 snap-frozen lung cancer tissues using quantitative reverse-transcriptase PCR. Moreover, we performed dual luciferase reporter assay and Western blot on 6 targeted genes (FZD8, ITGA10, ITPKB, LRP5, PIAS1 andRUNX1) in small cell lung carcinoma cell line NCI-H82. We also detected the effect of miR-375 on cell proliferation in NCI-H82. We found that miR-375 expression was significantly up-regulated in adenocarcinoma and small cell lung carcinoma but down-regulated in squamous cell carcinoma. Among the 22 putative target genes, 11 showed significantly different expression levels in at least 2 of 3 pair-wise comparisons (adenocarcinoma vs. normal, squamous cell carcinoma vs. normal or small cell lung carcinoma vs. normal). Six targeted genes had strong negative correlation with the expression level of miR-375 in small cell lung carcinoma. Further investigation revealed that miR-375 directly targeted the 3’UTR of ITPKB mRNA and over-expression of miR-375 led to significantly decreased ITPKB protein level and promoted cell growth. Thus, our study demonstrates the differential expression profiles of miR-375 in 3 subtypes of lung carcinomas and finds thatmiR-375 directly targets ITPKB and promoted cell growth in SCLC cell line.
Highlights
Lung cancer has long been the leading cause of cancer-related death in males worldwide[1]
Expression profiles of 723 human miRNAs were investigated in selected laser capture microdissection (LCM) cancerous cell populations and normal cells derived from 36 AC, 30 squamous cell carcinoma (SQ), 16
Up-regulation of miR-375 expression level was observed slightly in AC and significantly in small cell lung cancer (SCLC), while marked down-regulation of miR-375 expression was observed in SQ (Fig 1B and Table 2)
Summary
Lung cancer has long been the leading cause of cancer-related death in males worldwide[1]. NSCLC is a heterogeneous group comprised of 2 most common subtypes, i.e. squamous cell carcinoma (SQ) and adenocarcinoma (AC)[2].Despite the improvements in early diagnosis and recent breakthrough in chemo/targeted therapies, the overall 5-year survival rate of lung cancer remains low and the recurrence rate is high[3].Poor prognosis is due to late disease presentation, heterogeneities, and relatively limited understanding of tumor biology. MicroRNA (miRNA) is a class of endogenously expressed, noncoding small RNA with around 22 nucleotides. Many studies have demonstrated unique miRNA profiles in lung cancer [5,6,7].In our previous study on the investigation of miRNA biomarkers in 3 subtypes of lung carcinomas, we found significant up-regulation of the microRNA-375(miR375) expression levels in AC and SCLC but down-regulation of miR-375 in SQ [8]. We hypothesize that miR-375 may be a candidate oncogene in AC and SCLC but a tumor suppressor in SQ
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