Abstract
Abnormal proliferation and drug resistance are the hallmarks of lung adenocarcinoma (LAD). Dispite the advances in diagnosis and therapy, the 5-year survival remains low. Increasing studies regarding its pathological mechanism have been focused on microRNA (miRNA) due to its nodal regulatory properties. This study aims to characterize the expression of miR-432 in LAD and investigate its effects on the proliferation and sensitivity of lung cancer cells to cisplatin. Here, we report that downregulation of miR-432 in LAD tissues was correlated with a higher clinical stage (p = 0.03) and poor prognosis (p = 0.036). Additionally, miR-432 expression was negative correlated with high Ki67 labeling index (p = 0.016) in our cohorts. Functionally, over-expression of miR-432 inhibits cell proliferation through arresting cell cycle and sensitizes tumor cells to cisplatin. Mechanistically, miR-432 functions by directly targeting E2F3 and AXL, and they, in turn, mediate the regulation of miR-432 towards cell proliferation and cisplatin sensitivity. Importantly, miR-432 levels are negatively correlated with the levels of E2F3 and AXL in human LAD tissues. These results demonstrated that miR-432 functions as a tumor-suppressive miRNA and may represent a prognostic parameter and therapeutic target for LAD.
Highlights
Lung adenocarcinoma (LAD), is the most common histological subtype of non-small cell lung cancer and its incidence has increased markedly over the past few decades in many countries, including China [1]
To identify novel miRNA acting as tumor suppressor in LAD, we comparatively analyzed the expression of 25 miRNAs in three matched-pairs of primary tumor and its surrounding normal tissues
MiRNAs act as oncogene or tumor suppressor in various tumor and accumulating evidence suggests that miRNAs contribute greatly to the pathogenesis of LAD [19]
Summary
Lung adenocarcinoma (LAD), is the most common histological subtype of non-small cell lung cancer and its incidence has increased markedly over the past few decades in many countries, including China [1]. Previous studies have reported that miR-432 was depressed in various tumors, such as hepatocellular carcinoma, cervical and ovarian cancer [6,7,8]. MiR432 induces tumor suppression in hepatocellular carcinoma cells by targeting LRP6, TRIM29 and Pygo, which www.impactjournals.com/oncotarget subsequently deactivates Wnt/β-catenin signaling pathway. It could target the oncogene NESTIN/NES, RCOR1/COREST and MECP2 in neuroblastoma cells to induce neurite projections, arrest cells in G0-G1and reduce cell proliferation. Kaplan–Meier survival analyses showed that depressed miR-432 expression was correlated with cancer-specific death of LAD patients. And mechanistically, our in vitro and in vivo assays indicate that miR-432 overexpression could inhibite the cell proliferation and tumor formation of LAD. Our findings highlight the importance of miR-432 dysfunction in promoting tumor progression and chemoresistance and implicate miR-432 as a potential therapeutic target in lung cancer
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