Abstract
Incomplete understanding remains in the molecular mechanisms underlying progression and metastasis of renal cancer. The transcription factor SOX4 is upregulated in various human malignancies, including renal cancer, indicating it may be involved in renal tumorigenesis. In this study, we explored this hypothesis by loss-of-function and gain-of-function assays of SOX4 in renal cancer cell lines and renal epithelial cell line. We found that specific knockdown of SOX4 in renal cancer cell lines significantly suppressed the migration and invasion of cancer cells; specific overexpression of SOX4 in renal epithelial cell line markedly promoted the migration and invasion of the cell line. Epithelial-mesenchymal transition (EMT), a fundamental morphogenesis process, is implicated in renal cancer progression and metastasis. Our results demonstrated that SOX4 positively regulated the expression of mesenchymal cell markers and negatively regulated the expression of epithelial cell marker, and was involved in signal transduction pathway of TGFβ-induced EMT. In addition, SOX4 induced EMT probably through modulating the AKT/p-AKT signaling cascade. Finally, we found that SOX4 was significantly upregulated in clinical renal cancer samples compared with corresponding normal tissues and associated with EMT process in clinical samples. Taken together, our findings confirm a crucial function of SOX4 in the metastasis of renal cancer through orchestrating EMT and establish that the function suppression of SOX4-AKT-EMT axis might be an attractive therapeutic intervention during renal cancer metastasis.
Highlights
Renal cell carcinoma (RCC) accounting for 80-90% renal malignancies derives from renal tubule epithelium, which is called renal adenocarcinoma
Our previous findings demonstrated low miR129-3p levels were associated with short disease-free and overall survival of RCC patients. miR-129-3p impaired RCC cell migratory and invasive properties by decreased multiple metastasis-related genes, including SOX4 [29]
Immunofluorescence revealed that SOX4 was overexpressed in RCC cells compared with the normal renal cells (Fig. 1E)
Summary
Renal cell carcinoma (RCC) accounting for 80-90% renal malignancies derives from renal tubule epithelium, which is called renal adenocarcinoma. According to 2004 WHO histopathological classification criteria, RCC was classified into a variety of histologic subtypes. Clear cell RCC (ccRCC) represents the most common subtype of RCC that is characterized by high frequency of metastasis and mortality, and resistance to traditional radiotherapy and chemotherapy. Cancer metastasis is the overwhelming cause of tumor-related mortality in tumor-bearing patients [2,3,4]. Approximately 30% of patients with renal cancer have developed local invasion or distant metastasis when diagnosed, resulting in poor prognosis. The underlying molecular mechanisms of metastasis of renal cell carcinoma are elusive. It is greatly needed to make a thorough inquiry of metastatic mechanisms in RCC, aiming to provide a novel target for clinical treatment
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