title: Knockdown of Slit2 promotes growth and motility in gastric cancer cells via activation of AKT/β-catenin.
abstract: We previously showed that Slit2 was highly expressed in gastric cancer tissues that exhibit less advanced clinicopathological features, suggesting a tumor suppressor role for Slit2. In the present study, we investigated the effects of Slit2 knockdown on gastric cancer cells. Slit2-specific shRNAs were used to generate Slit2-knockdown SGC-7901 gastric cancer cells. Cell proliferation assay, Annexin V/PI double staining and cell cycle analysis were used to investigate the role of Slit2 knockdown in cell growth. Wound-healing and in vitro migration/invasion assays were performed. Subcutaneous tumor formation and peritoneal spreading in nude mice were employed to examine the in vivo effects of Slit2 knockdown. Cell signaling changes induced by Slit2 knockdown were analyzed by immunoblotting. Slit2 knockdown increased gastric cancer cell growth in monolayer and soft agar/Matrigel 3D culture. Slit2 knockdown inhibited apoptosis but did not alter cell cycle progression. Slit2-knockdown cells formed larger tumors and produced more peritoneal metastatic nodules in nude mice. Slit2 knockdown increased AKT phosphorylation, activated anti-apoptotic signaling, suppressed GSK3β activity and induced β-catenin activation. Blocking the effects of PI3K/AKT using pharmacological inhibitors abolished the ability of Slit2 knockdown to induce apoptosis resistance and cell migration/invasion. These results indicate that Slit2 knockdown promotes gastric cancer growth and metastasis through activation of the AKT/β‑catenin-mediated signaling pathway.
authors.affiliation: Department of General Surgery, Central Hospital of Shanghai Minhang District, Shanghai 201100, P.R. China.
authors.forename: Rongliang
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of General Surgery, Central Hospital of Shanghai Minhang District, Shanghai 201100, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Central Hospital of Shanghai Minhang District, Shanghai 201100, P.R. China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Central Hospital of Shanghai Minhang District, Shanghai 201100, P.R. China.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Central Hospital of Shanghai Minhang District, Shanghai 201100, P.R. China.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000098552:Slit Homolog 2 Protein