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MicroRNA-205 Promotes Cell Proliferation of Non-Small Cell Lung Cancer by Targeting Smad4

Yuanyuan Zeng, Jianjie Zhu, Xiaoxue Song, Sonia F Erfani, Hualong Qin, Zhe Lei, Dan Shen, Xiuwei H Yang, Zeyi Liu and Jian-an Huang

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancerrelated death worldwide. Despite recent advances in cancer diagnosis and treatment, the survival rate of NSCLC patients remains dismally low. There is an urgent need for better mechanistic understanding and development of novel diagnostic and treatment strategies against this malignant disease. MicroRNAs (miRNAs), a class of 19- to 24- base pair non-coding RNAs, have increasingly been implicated as crucial regulators of NSCLC malignancy, and promising biomarkers and/or therapeutic targets for such aggressive disease. Here, we report clinical, molecular, and functional studies of miR-205 in NSCLC. Our analyses of an NSCLC patient cohort showed that expression of miR-205 in primary tumors was 7-fold higher than their corresponding adjacent noncancerous tissues. However, miR-205 was not associated with tumor stage, smoking status, age, or gender, implying a functional link to earlystage tumorigenesis of NSCLC. To test this possibility, we turned our attention to Smad4, a putative target of miR-205 and a widely recognized tumor suppressor. As expected, the expression of Smad4 mRNA in primary tumors of our patient cohort was lower than their normal counterparts. Importantly, we detected a strong negative association between miR-205 and Smad4 in patient tumor tissues. With these clinical leads, we next evaluated the molecular and functional links between these two distinct types of molecules. Our initial mutagenesis analyses showed that miR-205 repressed the expression of Smad4 by directly targeting the 3’-UTR region of its mRNA. Subsequently, we found that overexpression of miR-205 enhanced the proliferation of cultured NSCLC cells. Conversely, siRNA-directed knockdown of Smad4 markedly suppressed tumor cell proliferation. Moreover, our MassARRAY technology-based analyses showed that the DNA methylation of the -77CpG site in the promoter region of miR-205 was significantly impaired in patient tumor tissues. Taken together, our study for the first time provides clinical, molecular and functional evidence on the critical roles of miR-205 in human NSCLC. In particular, our analyses demonstrate that miR-205 drives tumor cell proliferation of NSCLC by directly downregulating Smad4 expression. As such, our findings strongly support the potential of miR-205 as a candidate biomarker and therapeutic target for the diagnosis and treatment of NSCLC.