Abstract
SRC, also known as proto-oncogene c-Src, is a non-receptor tyrosine kinase that plays an important role in cancer progression by promoting survival, angiogenesis, proliferation, and invasion pathways. In this study, we found that SRC protein levels were consistently upregulated in lung cancer tissues, but that SRC mRNA levels varied randomly, suggesting that a post-transcriptional mechanism was involved in SRC regulation. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for miRNAs that potentially target SRC. We identified specific targeting sites for miR-203 in the 3′-untranslated region (3′-UTR) of SRC. We then experimentally validated miR-203 as a direct regulator of SRC using cell transfection and luciferase assays and showed that miR-203 inhibited SRC expression and consequently triggered suppression of the SRC/Ras/ERK pathway. Finally, we demonstrated that the repression of SRC by miR-203 suppressed the proliferation and migration and promoted the apoptosis of lung cancer cells. In summary, this study provides the first clues regarding the role of miR-203 as a tumor suppressor in lung cancer cells through the inhibition of SRC translation.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide, and non–small cell lung cancer (NSCLC) accounts for approximately 80% of all cases [1]
SRC regulates multiple signaling cascades associated with tumor development and progression, including the focal adhesion kinase (FAK) pathway, the epidermal growth factor receptor (EGFR) pathway, and the Ras/ERK pathway [7]
We found that the SRC protein level was higher in human lung adenocarcinoma A549 cells compared to that in normal lung fibroblast HLF cells (Figure S1, A and B in File S1), but the SRC mRNA level was equal in these two cell lines (Figure S1C in File S1)
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide, and non–small cell lung cancer (NSCLC) accounts for approximately 80% of all cases [1]. Dominant oncogenes and tumor suppressor genes involved in the pathogenesis of lung cancer have attracted substantial interest, and their central roles and fundamental contribution to the misbehavior of cancer cells have become clear [4]. These genes offer new targets for biological therapies. SRC functions as an oncogene to favor proliferation, migration, and invasion of various types of cancer cells [8,9] Despite these recent advances in our understanding of the important roles of SRC in tumorigenesis, the precise molecular mechanism through which SRC contributes to lung cancer progression remains to be fully elucidated
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