title: Autocrine and paracrine STIP1 signaling promote osteolytic bone metastasis in renal cell carcinoma.
abstract: Bone metastases are responsible for some of the most devastating complications of renal cell carcinoma (RCC). However, pro-metastatic factors leading to the highly osteolytic characteristics of RCC bone metastasis have barely been explored. We previously developed novel bone-seeking RCC cell lines by the in vivo selection strategy and performed a comparative proteome analysis on their total cell lysate. Here, we focused on STIP1 (stress-induced phosphoprotein 1), the high up-regulated protein in the bone-seeking cells, and explored its clinical relevance and functions in RCC bone metastasis. We observed high levels of both intracellular and extracellular STIP1 protein in bone metastatic tissue samples. Elevated STIP1 mRNA in the primary RCC tumors remarkably correlated with worse clinical outcomes. Furthermore, both human recombinant STIP1 protein and anti-STIP1 neutralizing antibody were used in the functional studies. We found that 1) STIP1 protein on the extracellular surface of tumor cells promoted the proliferation and migration/invasion of RCC tumor cells through the autocrine STIP1-ALK2-SMAD1/5 pathway; and 2) STIP1 protein secreted into the extracellular tumor stromal area, promoted the differentiation of osteoclasts through the paracrine STIP1-PrPc-ERK1/2 pathway. Increased cathepsin K (CTSK), the key enzyme secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption was further detected in the differentiated osteoclasts. These results provide evidence of the great potential of STIP1 as a novel biomarker and therapeutic target in RCC bone metastasis.
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R.China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R.China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R.China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R.China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R.China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R.China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056657:Cathepsin K / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D010010:Osteoclasts / Q000378:metabolism; D010014:Osteolysis; D019899:Paracrine Communication; D018621:PrPC Proteins / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D006360:Heat-Shock Proteins; D018621:PrPC Proteins; C079373:STIP1 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D056657:Cathepsin K
keywords: RCC bone metastasis; STIP1-ALK2-SMAD1/5 signaling; STIP1-prion-ERK1/2 signaling; stress-induced phosphoprotein 1(STIP1); tumor microenvironment