79109

MAPKAP1

mitogen-activated protein kinase associated protein 1;MAPKAP1;mitogen-activated protein kinase associated protein 1

MEKK2-interacting protein 1|SAPK-interacting protein 1|TORC2 subunit MAPKAP1|mSIN1|mitogen-activated protein kinase 2-associated protein 1|ras inhibitor MGC2745|stress-activated map kinase interacting protein 1|stress-activated map kinase-interacting prot

9q33.3

protein-coding

BACKGROUND: Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is essential for early embryonic development and is the key regulator of Akt, which plays an important role in various pathological conditions such as cancer. However, the biological function and clinical significance of SIN1 in hepatocellular carcinoma (HCC) remains unknown. METHODS: Real-time quantitative reverse-transcriptase polymerase chain reaction analysis, western blot analysis, and immunohistochemical staining were used to test the expression level of SIN1, and its correlation with clinicopathologic parameters as well as the prognosis for patients with HCC were analyzed. In addition, the biological function and molecular mechanisms of SIN1 in HCC were investigated. RESULTS: SIN1 levels were elevated predominantly in HCC tissues, and its level in solitary large HCC was significantly lower than those in nodular HCC (P = .016), but showed no significant differences between solitary large HCC and small HCC (P > .05). Levels of SIN1 were up-regulated in highly metastatic HCC cell lines (HCCLM3 and MHCC97-H), whereas their invasion and migration significantly decreased after depletion of SIN1. High expression of SIN1 was associated with tumor number (P = .012), capsular formation (P = .037), and venous invasion (P = .023) and was an independent risk factor for overall survival (P = .046). Finally, SIN1 was capable of promoting invasion and metastasis of HCC by facilitating epithelial-mesenchymal transition. CONCLUSIONS: The current findings suggest that SIN1 plays an important role in HCC invasion and metastasis by facilitating epithelial-mesenchymal transition.

Approximately 30% of patients with renal cell carcinoma (RCC) develop bone metastasis, which is characterized by extensive osteolysis leading to severe bone pain and pathologic fracture. Although the mechanism of RCC-induced osteolysis is unknown, studies of bone metastasis have shown that tumor-induced changes in bone remodeling are likely mediated by alterations in the bone microenvironment. Here, we report the discovery of a novel osteoclast stimulatory factor secreted by RCC bone metastasis (RBM). Through microarray analysis, we found expression of the chemokine, macrophage inflammatory protein-1 delta (MIP-1 delta), to be increased in RBM versus patient-matched primary RCC tissues and confirmed this finding by quantitative reverse transcription-PCR (qRT-PCR) and ELISA (P < 0.05). Furthermore, MIP-1 delta expression in RBM tissues was significantly (P < 0.001) higher than in human bone marrow, suggesting a potential alteration of the bone microenvironment. The receptors for MIP-1 delta, CCR1 and CCR3, were expressed in both osteoclast precursors and mature, bone-resorbing osteoclasts as shown by qRT-PCR and Western analysis. In functional studies, MIP-1 delta stimulated chemotaxis of two osteoclast precursor cell types: murine bone marrow mononuclear cells (BM-MNC) and RAW 264.7 cells. Furthermore, MIP-1 delta treatment of murine calvaria caused increased bone resorption as determined by measurement of released calcium. Correspondingly, MIP-1 delta significantly enhanced osteoclast formation and activity in response to RANKL in both BM-MNC and RAW 264.7 cells. Taken together, these data suggest that MIP-1 delta expression is increased in RBM relative to RCC and bone marrow, and may promote RBM-induced osteolysis by stimulating the recruitment and differentiation of osteoclast precursors into mature osteoclasts.