Sonic Hedgehog Pathway Promotes Gastric Cancer Cell Growth And Proliferation

The Hedgehog (Hh) family of secreted signaling proteins plays a critical role in the development of diverse animal phyla, from Drosophila to humans, regulating morphogenesis of a variety of tissues and organs. Hh signaling is also involved in the control of stem cell proliferation in adult tissues and the aberrant activation of the Hh pathway has been linked to multiple types of human cancer. A lot has happened since the initial discovery and the molecular cloning of Drosophila Hh. Many components involved in Hh signal transduction in Drosophila have since been identified and characterized. However, the vertebrate Hh signaling pathway may yet offer some surprises.The hedgehog signaling pathway plays an essential role during pattern generation and embryonic pattern formation in mammalian. Three hedgehog genes have been founded and described in mammals:Sonic hedgehog(SHH), Indian hedgehog (IHH), and Desert hedgehog (DHH).All of them are involved in embryogenesis, organogenesis and tumor development. And the study of SHH signaling pathway is the most thorough among them. There are several proteins involved in an integral SHH signaling pathway, such as the transmembrane protein receptor Patched (PTCH), transmembrane protein Smoothened (SMOH), the transcription factor GLI and cytoplasmic proteins Fused and Suppressor of Fused [Su(Fu)]. Misregulation of sonic hedgehog signaling and mutations of SHH pathway components have been related to the initiation and growth of different malignant tumors. Increasing our understanding of the cell-specific mechanisms that control SHH signaling could provide clues to understand the relationship between regulated proliferation and uncontrolled neoplasia in adult tissues.The sonic hedgehog signaling pathway exists in most tumors and plays a key role in cancer cell proliferation, differentiation and survival, such as basal cell carcinomas, prostate cancer, lung cancer, oral cancer and digestive tract tumors, In recent years, many studies have shown that the aberrant activation of SHH signaling pathway is closely related with the generation and development of gastric tumors. In this study we focused on primary gastric tumors gam-016which got from enzyme digestion and gastric tumor cell line MKN-45, and explore how the SHH pathway affect gastric tumor growth and cell proliferation and further reveal the regulatory mechanism. Previous study showed that when the sonic hedgehog pathway was inhibited by drug cyclopamine will led to a inhibition on the gastric cancer cell growth and proliferation, it means that the sonic hedgehog pathway can promote cell growth and proliferation, after the research on the functional mechanism we also found that the sonic hedgehog pathway involved in the regulation of the cell cycle and survival of gastric cancer cells: first, the inhibition of SHH pathway induced G1-arrest of the cell cycle and blocking the entry from Gl phase to S phase, Second, drug cyclopamine treatment accelerated cell death. As we know that the cell cycle and survival are regulated directly by the Corresponding protein factors. Therefor we speculated that SHH pathway might regulated gastric tumor cell cycle and survival indirectly by affecting the expression levels of these protein factors; Finally, in order to explore the relationship between SHH pathway and gastric tumor growth, we established NOD/SCID mice xenograft model of gastric tumor and found that blocking the SHH pathway in tumor bearing NOD/SCID mice induced tumor regression significantly, this result has important clinical meaning on the treatment of gastric cancer, and suggesting that targeting the SHH pathway can be a novel approach for the treatment of gastric cancer.