Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma

Abstract

BackgroundAlthough metastasis of clear cell renal cell carcinoma (ccRCC) is predominantly observed in late stage tumors, early stage metastasis of ccRCC can also be found with indefinite molecular mechanism, leading to inappropriate clinical decisions and poor prognosis. Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in calcium/phosphate homeostasis, which regulates various cellular processes in normal development and tumorigenesis. This study aimed to investigate the role and mechanism of regulation of STC1 in the metastasis of early stage ccRCC.MethodsSTC1 mRNA and protein expression was determined in ccRCC surgical specimens, RCC cell lines, and human kidney tubule epithelial cell line HKC by real-time polymerase chain reaction (RT-PCR) and western blotting. Immunohistochemistry staining (IHC) and immunofluorescence were also used to examine the expression and localization of STC1 in ccRCC tissues and cancer cells. Knockdown and overexpression studies were conducted in vitro in RCC cell lines using small interfering RNAs (siRNA) and lentiviral-mediated gene delivery to evaluate the role of STC1 in cell proliferation, anchorage-dependent and independent growth, cell cycle control, and migration and invasion.ResultsSTC1 mRNA and protein expression were significantly up-regulated in tumors when compared with non-tumor tissues, with the greatest increase in expression observed in metastatic tissues. Clinicopathological analysis revealed that STC1 mRNA expression was associated with Fuhrman tumor grade (P = 0.008) and overall Tumor Node Metastasis (TNM) staging (P = 0.018). STC1 expression was elevated in T1 stage metastatic tumors when compared with localized tumors, and was positively correlated with average tumor diameter. Silencing of STC1 expression by Caki-1 and A498 resulted in the inhibition of cell proliferation, migration, and invasion, meanwhile down-regulation of STC1 impaired epithelial–mesenchymal transition (EMT) of ccRCC cell lines. Overexpression of STC1 in Caki-2 enhanced cell growth and proliferation but not migration and invasion. Further investigation identified hypoxia and HIF-1α as candidate regulators of STC1 expression.ConclusionsOur findings demonstrate a role for STC1 in metastasis of early stage ccRCC and suggest that STC1 may be a biomarker of potential value both for the prognosis of this disease and for guiding clinical decisions regarding surgical strategies and adjuvant treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0421-4) contains supplementary material, which is available to authorized users.

Stanniocalcin‐1 mediates negative regulatory action of epidermal layer on expression of matrix‐related genes in dermal fibroblasts

“…24 Although the factor(s) mediating this action has not been identified, it is known that the JNK-AP1 pathway is induced in dermal fibroblasts. 17 These results are consistent with our findings in this study that STC1 activates the JNK-AP1 pathway to induce MMP1 in dermal fibroblasts. A further study is needed to confirm the intracellular signaling pathway of STC1 in SCC, but our results suggest that STC1 may be a key regulator of MMP1.…”

“…SCC cells have been reported to increase MMP1 in the adjacent dermal layer . Although the factor(s) mediating this action has not been identified, it is known that the JNK–AP1 pathway is induced in dermal fibroblasts . These results are consistent with our findings in this study that STC1 activates the JNK–AP1 pathway to induce MMP1 in dermal fibroblasts.…”

“…It is also related to metastasis of renal cancer . Furthermore, in renal carcinoma cells, inhibition of STC1 expression reduced invasive activity . Thus, STC1 secretion may regulate invasion of epithelial cells into the connective tissue layer.…”

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

“…XbaI and EcoRI were used to generate pLV-EGFP-KLF6. Lentivirus-encoding DNA was packaged as previously described (21). For knockdown of KLF6 and E2F1, siKLF6#2 and siE2F1 sequences were cloned into the pLVshRNA-EGFP-(2A)Puro vector.…”

STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells

“…Recent studies found that STC1 is expressed abundantly in a variety of mammalian tissues including kidney [7], heart [8], lung [9], ovary [10], brain [11], muscular and skeletal tissues [12]. STC1 is highly conserved during evolution, and is implicated in several physiologies and pathologies, such as pregnancy [13], angiogenesis [14], inflammation and apoptosis [15].…”