Background: Non-small cell lung cancer (NSCLC) is a common and fatal cancer worldwide with a very low 5-year overall survival rate. Ribonucleotide reductase M2 subunit (RRM2), a small subunit of the ribonucleotide reductase complex, has been found to be an oncogenic role in a variety of tumors including NSCLC. However, the regulatory mechanism of RRM2 in NSCLC is not clear. Increasing evidence suggests that non-coding RNAs (ncRNAs) including miRNAs and lincRNAs may promote or inhibit tumor initiation and development through regulating the expression of oncogenic genes. It is interesting to find ncRNAs which play important role in regulating RRM2 expression. Materials and methods: The expression levels of RRM2, LINC0066 and miR-143-3p in NSCLC tumor tissues and cell lines were detected using qRT-PCR. The regulatory relationships among RRM2, LINC0066 and miR-143-3p were predicted using database analysis and verified by luciferase reporter assay and RIP analysis. The proliferation ability of NSCLC cells was assessed using CCK8 and colony formation assays. The expression of related proteins was determined by Western blot. In vivo effect of RRM2, LINC0066 and miR-143-3p to NSCLC were detected through xenograft experiments. Results: In this study, we found RRM2 was upregulated in NSCLC tumor and cell lines, and the aberrant upregulation predicted a poor prognosis. Then, we predicted and confirmed that RRM2 was negatively regulated by miR-143-3p. Further study implied that LINC00667 acted as a ceRNA by sponging miR-143-3p and regulated RRM2 expression indirectly. Moreover, we found that the growth of NSCLC was regulated by LINC00667/miR-143-3p/RRM2 signal pathway both in vitro and in vivo. LINC00667 and RRM2 promoted the tumor growth while miR-143-3p inhibited it. Conclusion: Our study revealed a LINC00667/miR-143-3p/RRM2 signal pathway that played an important role in the progress of NSCLC, which might be potential therapeutic targets for NSCLC.

Abstract. Increasing evidence has indicated that the abnormal expression of microRNAs contributes to tumorigenesis and tumor development. Understanding the roles of microRNAs in non-small cell lung cancer (NSCLC) might provide valuable information for therapeutic strategies in the therapy for patients with NSCLC. In the present study, significant upregulation of microRNA (miR)-301a was observed in NSCLC tissues and cell lines compared with normal adjacent tissues and a normal human bronchial epithelial cell line. The inhibition of miR-301a suppressed proliferation, migration and invasion of NSCLC cells. Functional analyses indicated that DLC1 was a direct target of miR-301a in NSCLC. Inhibiting miR-301a expression decreased DLC1 expression at mRNA and protein levels. Moreover, DLC1 knockdown partially reversed the inhibition of proliferation, migration and invasion induced by miR-301a knockdown in NSCLC cells. Therefore, these findings may provide novel insights into the molecular mechanisms of miR-301a in proliferation, migration and invasion of NSCLC cells. The findings also indicated that miR-301a may act as a novel potential therapeutic target for patients with NSCLC.

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