Possible Role of Sonic Hedgehog and Epithelial-Mesenchymal Transition in Renal Cell Cancer Progression

Abstract

PurposeSonic hedgehog (Shh) signaling and epithelial-mesenchymal transition (EMT) are both known to relate to cancer progression. The purpose of this study was to investigate the role of Shh signaling and EMT in renal cell carcinoma (RCC).Materials and MethodsCell proliferation was assayed in RCC cell lines in the presence or absence of a Shh signaling stimulator, recombinant Shh (r-Shh) protein, or a Shh signaling inhibitor, cyclopamine. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to study the expression of EMT markers (E-cadherin, N-cadherin, and vimentin) and osteonectin. The expression of Ki-67, Gli-1, osteonectin, and EMT markers in nephrectomy specimens from RCC patients was also measured by immunohistochemical (IHC) staining.ResultsRCC cells showed enhanced cell proliferation by r-Shh protein, whereas cell proliferation was suppressed by the addition of cyclopamine in RenCa cells. Real-time RT-PCR showed that r-Shh suppressed the expression of E-cadherin and that this suppression was partly blocked by cyclopamine alone in RenCa cells. In the IHC results, osteonectin significantly correlated with vein sinus invasion (p=0.0218), and the expression of vimentin significantly correlated with lymphatic invasion (p=0.0392).ConclusionsShh signaling and EMT play roles in RCC progression, and the Shh signaling inhibitor cyclopamine might be a possible molecular targeted therapeutic strategy for RCC.

Anti-fibrotic and Anti-tumorigenic Effects of Rhein, a Natural Anthraquinone Derivative, in Mammalian Stellate and Carcinoma Cells

“…In this regard, the administration of rhein provided a decent suppressive effect. In addition to its role in fibrogenesis, SHH is suggested as a prominent switch to an accelerated progression of cancer and metastasis (Behnsawy et al , , Grzelak et al , ). In the study of Sherman and Zavros, aberrant SHH expression was found in the development of chronic gastric inflammation and the progression to gastric cancer post H. pylori infection (Sherman and Zavros, ).…”

Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

“…For example, in thyroid cancer, SHH is expressed in 64% of PTC tissues but only in 17% of non-cancerous tissues, and GLI1 is expressed in 48% and 9% of these two different types of tissues, respectively [ 115 ]. Activation of the SHH pathway is related to promotion of the EMT process in lung cancer cell lines [ 116 ], renal cell cancer [ 117 ], and gastric cancer [ 91 ]. Based on these observations, blocking SHH signaling is a popular strategy in cancer therapy.…”

Elucidating steroid alkaloid biosynthesis in Veratrum californicum: production of verazine in Sf9 cells

“…Cyclopamine was discovered to inhibit the Hedgehog signaling pathway by direct binding to the G protein‐coupled receptor Smoothened (Chen et al ., ). As such, cyclopamine has shown promising antineoplastic activities against several cancers in which Hedgehog signaling malfunction is implicated, including pancreatic cancer, renal cell carcinoma, medulloblastoma, basal cell carcinoma, and leukemia (Gailani et al ., ; Taipale et al ., ; Berman et al ., ; Olive et al ., ; Lin et al ., ; Bahra et al ., ; Behnsawy et al ., ). A semi‐synthetic analog of cyclopamine, IPI‐926, has been in clinical trials for treatment of several cancers including pancreatic cancer and leukemia (Olive et al ., ; Tremblay et al ., ; Lin et al ., ).…”