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.
Highlights
RCC is one of the ten most common cancers in adults, and clear cell RCC represents 85% of these cases [1]
It is known as transformation-sensitive protein IEF SSP 3521, a protein overexpressed in transformed cells, and HSP70/HSP90organizing protein (HOP), a protein involved in heat shock response
We obtained the enriched bone-seeking RCC cell line OS-RC-2-BM5 from in vivo selection [12], and here we detected a remarkably high expression of STIP1 on the cell surface membrane which led to the secretion of STIP1 protein into the culture medium, indicating a possible autocrine effect of STIP1 on the bone-seeking tumor cell itself
Summary
RCC is one of the ten most common cancers in adults, and clear cell RCC represents 85% of these cases [1]. The number of RCC diagnoses has increased by ~40% over the past three decades, but the overall 5-year overall survival rates have improved very little in that time The 5-year survival rate for metastatic RCC is less than 10% [2]. RCC bone metastasis, the second most common site for RCC following lung [3, 4], is aggressive and destructive, as it causes more skeletal-related events (SREs) than bone metastases from other cancers, especially pathological fracture, spinal cord and nerve root compression, and hypercalcemia [5, 6]. While new targeted therapies have significantly increased patient survival, bone has become a sanctuary site in RCC [7]. The understanding of bone metastasis in RCC is, becoming increasingly important to facilitate the development of preventive and therapeutic strategies
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