Eight proteins play critical roles in RCC with bone metastasis via mitochondrial dysfunction

Abstract

Most kidney cancers are renal cell carcinomas (RCC). RCC lacks early warning signs and 70 % of patients with RCC develop metastases. Among them, 50 % of patients having skeletal metastases developed a dismal survival of less than 10 % at 5 years. Therefore, exploring the key driving proteins and pathways involved in RCC bone metastasis could benefit patients’ therapy and prolong their survival. We examined the difference between the OS-RC-2 cells and the OS-RC-2-BM5 cells (subpopulation from OS-RC-2) of RCC with proteomics. Then we employed Western-blot, immunohistochemistry and the clinical database (oncomine) to screen and verify the key proteins and then we analyzed the functions and the related pathways of selected key proteins with system biology approaches. Our proteomic data revealed 26 significant changed spots (fold change <0.5 and >1.9, P < 0.05) between two cells. The Western blotting results validated for these identified spots were consistent with the proteomics’. From the public clinical database, 23 out of 26 proteins were connected with RCC metastases and 9 out of 23 with survival time directly (P < 0.05). Finally, only 8 out of 9 proteins had significantly positive results in tissues of RCC patients with bone metastasis compared with primary tumor (P < 0.05). System biology analyzing results showed these eight proteins mainly distributed in oxidative phosphorylation which indicates that mitochondria dysfunction played the critical role to regulate cells metastasis. Our article used a variety of experimental techniques to find eight proteins which abnormally regulated mitochondrial function to achieve a successful induction for RCC metastasis to bone.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-015-9731-4) contains supplementary material, which is available to authorized users.

Autocrine and paracrine STIP1 signaling promote osteolytic bone metastasis in renal cell carcinoma

“…In our previous proteome analysis of the total cellular protein from RCC tumor cells, STIP1 protein was found to be 4-fold more abundant in the bone-seeking cells than in the control parental cells [12], and STIP1 was observed to be translocated to the cell surface and secreted out of cells [13, 14], which may mediate extracellular tumor-niche interactions. To further define the subcellular location of the increased STIP1 protein, and study whether tumor cells actively secrete STIP1 protein, we conducted two experiments and found First, After culturing RCC tumor cells were cultured in serum-free medium for 24 h, we observed that the culture media clearly contained STIP1 but no intracellular GAPDH protein (Figure 1A).…”

“…Under the normal monolayer culture condition, both MTT assay and flow cytometry cell cycle analysis revealed that the bone-seeking cells proliferated faster than the parental cells [11, 12]. To test whether STIP1 modulates the proliferation of tumor cells, we added human recombinant STIP1 (hrSTIP1) to the culture media.…”

“…Based on this rationale, we used the previously reported in vivo selection strategy and developed novel bone-seeking clear cell RCC cell lines (OS-RC-2-BM5 and ACHN-BM5) [11, 12]. To characterize the molecular factors that endow RCC tumor cells with the ability to survive and cause lytic bone metastases, we performed a comprehensive proteome analysis on the bone-seeking RCC cells in comparing with their corresponding parental cells [12].…”

“…Based on this rationale, we used the previously reported in vivo selection strategy and developed novel bone-seeking clear cell RCC cell lines (OS-RC-2-BM5 and ACHN-BM5) [11, 12]. To characterize the molecular factors that endow RCC tumor cells with the ability to survive and cause lytic bone metastases, we performed a comprehensive proteome analysis on the bone-seeking RCC cells in comparing with their corresponding parental cells [12]. We focused on the protein level analysis rather than mRNA, because 1) we reasoned that the interplay between tumor cells and bone cells are largely mediated by secretory proteins, and 2) the protein analysis is more indicative to reveal corresponding cellular alterations than changes in mRNA levels.…”

MicroRNA-125b Suppresses Ovarian Cancer Progression via Suppression of the Epithelial-Mesenchymal Transition Pathway by Targeting the SET Protein

“…This inhibition was most likely accomplished by masking the histone lysines from acetylation, consequently silencing HATdependent transcription [16]. The knockdown of SET inhibits cell migration and invasion by increasing the activity and expression of PP2Ac and decreasing the expression of matrix metalloproteinase 9 (MMP-9) [17]; low levels of SET expression are associated with bone metastasis in renal cell carcinoma [18]. Therefore, using a bioinformatics prediction, we found that SET was a potential target of miR-125b; therefore, we sought to assess the expression of miRNA, its effect in human EOC, and its association with SET expression and epithelial-mesenchymal transition (EMT) in human EOC.…”