Abstract
Simple SummaryMicrophthalmia-associated transcription factor (MITF) has been reported to play a role in the progression of melanoma and other cancer types. However, the biological role of MITF in clear cell renal cell carcinoma (ccRCC) is largely unknown. In this study, we elucidate the role of MITF in the progression of ccRCC. MITF- and MITF-mediated signaling pathways were investigated in ccRCC cell through MITF knockdown as well as overexpression of MITF in vitro and in vivo. MITF contributed to cell proliferation, migration, invasion and tumor growth in ccRCC through activation of the RhoA/YAP signaling pathways. This study suggests that MITF has potential as a therapeutic target in ccRCC.Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor involved in the lineage-specific regulation of melanocytes, osteoclasts and mast cells. MITF is also involved in the progression of melanomas and other carcinomas, including the liver, pancreas and lung. However, the role of MITF in clear cell renal cell carcinoma (ccRCC) is largely unknown. This study investigates the functional role of MITF in cancer and the molecular mechanism underlying disease progression in ccRCC. MITF knockdown inhibited cell proliferation and shifted the cell cycle in ccRCC cells. In addition, MITF knockdown reduced wound healing, cell migration and invasion compared with the controls. Conversely, MITF overexpression in SN12C and SNU482 cells increased cell migration and invasion. Overexpression of MITF activated the RhoA/YAP signaling pathway, which regulates cell proliferation and invasion, and increased YAP signaling promoted cell cycle-related protein expression. Additionally, tumor formation was impaired by MITF knockdown and enhanced by MITF overexpression in vivo. In summary, MITF expression was associated with aggressive tumor behavior, and increased the migratory and invasive capabilities of ccRCC cells. These effects were reversed by MITF suppression. These results suggest that MITF is a potential therapeutic target for the treatment of ccRCC.
Highlights
Renal cell carcinoma (RCC) is the most common form of kidney cancer; it typically originates from renal tubular epithelial cells and accounts for about 2–3% of all malignancies in adults [1]
These findings suggest that suppressing Microphthalmia-associated transcription factor (MITF) significantly inhibited cell growth via a cell cycle shift in the Clear cell RCC (ccRCC)
We demonstrated that MITF plays an important role in the progression of ccRCC
Summary
Renal cell carcinoma (RCC) is the most common form of kidney cancer; it typically originates from renal tubular epithelial cells and accounts for about 2–3% of all malignancies in adults [1]. About 30% of ccRCC patients eventually develop metastasis, and less than 10% of these patients survive for 5 years or more after diagnosis [5]. Yes-associated protein (YAP) is a key effector of the Hippo pathway. The Hippo–YAP pathway is directly involved in cancer development and regulates many genes that function in survival and the epithelial–mesenchymal transition (EMT), among other processes [13,14]. This makes YAP inhibition an attractive target for cancer prevention and treatment [15,16]
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