Abstract
RASSF1C functions as an oncogene in lung cancer cells by stimulating proliferation and migration, and reducing apoptosis. Further, RASSF1C up-regulates important protein-coding and non-coding genes involved in lung cancer cell growth, including the stem cell self-renewal gene, piwil1, and small noncoding PIWI-interacting RNAs (piRNAs). In this article, we report the identification of microRNAs (miRNAs) that are modulated in lung cancer cells over-expressing RASSF1C. A lung cancer-specific miRNA PCR array screen was performed to identify RASSF1C target miRNA-coding genes using RNA isolated from the lung cancer cell line H1299 stably over-expressing RASSF1C and corresponding control. Several modulated miRNA genes were identified that are important in cancer cell proliferation and survival. Among the miRNAs down-regulated by RASSF1C is miRNA-33a-5p (miRNA-33a), which functions as a tumor suppressor in lung cancer cells. We validated that over-expression of RASSF1C down-regulates miR-33a expression and RASSF1C knockdown up-regulates miR-33a expression. We found that RASSF1C over-expression also increases β-catenin, vimentin, and snail protein levels in cells over-expressing miR-33a. In addition, we found that RASSF1C up-regulates the expression of ABCA1 mRNA which is a known target of miR-33a. Our findings suggest that RASSF1C may promote lung epithelial mesenchymal transition (EMT), resulting in the development of a lung cancer stem cell phenotype, progression, and metastasis, in part, through modulation of miR-33a expression. Our findings reveal a new mechanistic insight into how RASSF1C functions as an oncogene.
Highlights
Lung cancer is the most common and lethal of all cancers in the United States [1]
In previous work we have shown that RASSF1C appears to function as an oncogene in lung cancer cells, in part, through a novel RASSF1C-PIWIL1piRNA pathway which may promote cancer stem cell growth and progression
To further our understanding of how RASSF1C acts as an oncogene, we assessed the impact of RASSF1C on miRNA gene expression
Summary
Lung cancer is the most common and lethal of all cancers in the United States [1]. Our laboratory has focused on the pro-oncogenic activities of the Ras Association Domain Family Member 1 (RASSF1) gene. While RASSF1A is a well characterized tumor suppressor [2,3,4,5,6], the RASSF1C isoform appears to function as an oncogene promoting lung cancer cell proliferation, migration, and survival [7,8,9,10,11,12]. In previously published work we showed that RASSF1C regulates the expression of PIWIL1, a stem cell renewal gene, and small non-coding PIWI-interacting. This suggests that RASSF1C may promote lung cancer stem cell (CSC) development and progression, in part, through a novel PIWIL-piRNA pathway [7, 12, 19]. We have identified several novel RASSF1C target piRNA genes with either potential tumor-promoting or tumor-suppressing functions [12]. We showed that RASSF1C may modulate PIWIL1piRNA gene expression, in part, through promoting ERK1/2 phosphorylation and attenuating the AMPK pathway and downstream effectors p21 and p27 [8, 10, 12]
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