Abstract
Previous studies indicated a role of hepatocellular carcinoma-related protein-1(HCRP-1) in human cancers, however, its expression pattern in renal cell carcinoma (RCC) and the molecular mechanism of HCRP-1 on cancer progression have not been characterized. In the present study, HCRP-1 expression was examined in a RCC tissue microarray. The negative expression of HCRP-1 was significantly correlated with tumor grade (P = 0.002), TNM stage (P = 0.001) and pT status (P = 0.003). Furthermore, we showed a strong correlation between negative HCRP-1 expression and worse overall and disease-specific survival (P = 0.0003 and P = 0.0012, respectively). Knockdown of HCRP-1 promoted cell migration and invasion in 786-O and OS-RC-2 cell lines. HCRP-1 depletion increased matrix metalloproteinase (MMP)-2 protein level, with increased extracellular signal-regulatedkinase (ERK) phosphorylation, which could be reversed by ERK siRNA or ERK inhibitor, PD98059. Further analysis showed that HCRP-1 knockdown induced epidermal growth factor receptor (EGFR) phosphorylation. Treatment with EGFR inhibitor or EGFR siRNA blocked HCRP-1-mediated up-regulation of EGFR, ERK phosphorylation and MMP-2 expression. In summary, our results showed that negative HCRP-1 expression is an independent prognostic factor for RCC patients and promotes migration and invasion by EGFR-ERK-mediated up-regulation of MMP-2. HCRP-1 may serve as a therapeutic target for RCC.
Highlights
renal cell carcinoma (RCC), the third most common urologic cancer, is a very aggressive disease that accounts for about 3% of all malignancies and 90% to 95% of kidney neoplasm[1,2]
Because low HCRP-1 expression is associated with poor prognosis, supporting HCRP-1 may play an important role in one or more steps of tumor metastasis, we investigated the involvement of HCRP-1 in RCC cells migration and invasion
There has been evidence indicating an important role for HCRP-1 in cancer development in some malignancies, such as ovarian cancer, hepatocellular cell carcinoma (HCC) and breast cancer
Summary
RCC, the third most common urologic cancer, is a very aggressive disease that accounts for about 3% of all malignancies and 90% to 95% of kidney neoplasm[1,2]. HCRP-1, known as vacuolar protein sorting 37 homologue A (hVps37A), is located on the short arm of chromosome 811 For this region, 8p22, loss of heterozygosity (LOH) occurs to a high frequency in several human cancers including RCC12. Low HCRP-1 expression is proved to be of adverse prognostic significance in patients with oropharyngeal squamous cell carcinoma (OOSCC) who received preoperative chemoradiotherapy[15]. These studies indicate that HCRP-1 plays an important role in cancer progression with function as a tumor suppressor. We provided evidence that HCRP-1-knockdown up-regulated MMP-2 expression through the EGFR-ERK signaling pathway in this process
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