Possible role of the RhoC/ROCK pathway in progression of clear cell renal cell carcinoma

Abstract

To clarify the role of the Rho small GTP-binding protein (Rho) and its major downstream target, ROCK (Rho-associated serine-threonine protein kinase), in progression of renal cell carcinoma (RCC), we examined mRNA expression for Rho and ROCK genes in surgical specimen of RCC tissues from 78 Japanese patients and in the corresponding non-tumor tissues originating from the same patient using a real-time reverse transcription polymerase chain reaction (RT-PCR). Expression of mRNA for RhoA did not differ between tumor and non-tumor tissues. RhoB mRNA expression was higher in the tumor (P < 0.05), but expression was not associated with tumor grade, stage, or prognosis. However, degree of RhoC and ROCK mRNA expression was related to tumor grade (P < 0.05) and stage (P < 0.0001). A positive relationship was seen between expression of mRNA for RhoC and that for ROCK in tumor tissues (P < 0.0001). Kaplan-Meier plots showed high RhoC and ROCK mRNA expression to be negatively associated with overall survival (P < 0.0001). Multivariate analysis showed mRNA expression of RhoC and ROCK to be independent poor prognostic factors concerning overall survival. Our findings implicate the RhoC/ROCK pathway in carcinogenesis and progression of RCC, indicating that RhoC/ROCK may be a useful prognostic marker and a possible molecular target for treatment of the disease.Annual estimates of new diagnoses of renal cell carcinoma (RCC) are increasing steadily (17). RCC is resistant to chemotherapy and radiotherapy (17,28,29), while immunotherapy with interferon and/or interleukin (IL)-2 achieves responses in 10% to 20% of advanced RCC (17, 18). Although surgical resection of the primary tumor for patients remains the mainstay of therapy, RCC is characterized by a high proportion of cases with metastases present at diagnosis or appearing as a relapse following nephrectomy. Patients with distant metastases have a poor prognosis, with a 5-year survival rate of less than 10% in stage IV disease (17). Although inhibition of metastases logically would be a promising treatment strategy in advanced RCC, much of the molecular mechanism of progression and metastasis in RCC is yet to be eluidated.Cell migration is central to metastasis of malignant tumors (20). The Rho small GTP-binding protein (Rho) regulates formation of stress fibers, focal adhesions, and cell migration through reorganization of the actin cytoskeleton (7,25). Overexpression of Rho in human cancer tissues in comparison to nontumor tissues has been reported, with higher expression of Rho correlating with higher stage (6,13,24). Several lines of evidence directly link Rho to acquisition of a migratory, invasive, and metastatic phenotype (2, 3). Furthermore, Rho-kinase (ROCK), one of the major downstream effectors of Rho, induces stress-fiber formation and assembly for focal contact by regulating contractility of the actin-myo-

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

“…Although RhoA and RhoB expression levels were not significantly associated with patient clinicopathologic findings, RhoC overexpression has been shown to play a role in tumor invasion and correlates with a poor patient prognosis (31). The RhoC-ROCK1 signaling pathway plays a pivotal role in actin cytoskeleton organization and is involved in many key processes, including cell adhesion, vesicular trafficking, proliferation, cell survival, cell morphology, and cell-matrix interactions (32)(33)(34)(35)(36)(37). Inhibition of ROCK1 expression blocks LIMK2/cofilin phosphorylation and subsequent stress fiber formation (38,39).…”

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

“…In a number of cancers (breast, bladder, liver, melanoma and others) the ROCK2 pathway is implicated in the metastatic process [21, 25]. In both bladder and renal cancers, an elevation of ROCK2 expression has been associated with tumor invasion, metastasis, and an unfavorable prognosis [2, 16]. Moreover, the ROCK2 inhibitor Fasudil has been shown to suppress cell proliferation and migration of urothelial cancer cells [1].…”

Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress

“…These observations suggest a crucial role of Beclin1 during autophagy and tumor suppression. Related to this, ROCK1 overexpression has also been observed in a number of cancers and is associated with poor prognosis 27–29 . Furthermore, activating ROCK1 somatic mutations were identified in human cancers 30 .…”