Abstract
Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease.
Highlights
Lung cancer (non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)) is the leading cause of cancer-related deaths among men and women in developed countries, including Japan
We focused on miR-143-5p and demonstrated the tumor-suppressive functions of this miRNA, similar to those of miR-143-3p, in lung adenocarcinoma (LUAD) cells
One-way analysis of variance and Tukey tests for post hoc analysis were applied. These analyses were performed with GraphPad Prism 7 (GraphPad Software, La Jolla, CA, USA) and JMP Pro 14 (SAS Institute Inc., Cary, NC, USA). This is the first report revealing that miR-143-5p had tumor-suppressive functions in LUAD cells
Summary
Lung cancer (non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)) is the leading cause of cancer-related deaths among men and women in developed countries, including Japan. Based on the mutation statuses of cancer cells, several molecular targeted drugs have been available (e.g., epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors), and these treatments have dramatically improved patient outcomes [4,5]. These treatment effects are limited because acquired resistance and cancer recurrence occur in almost all patients [6]
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