Semaphorin 3 C enhances putative cancer stemness and accelerates peritoneal dissemination in pancreatic cancer

Cancer Cell International

Research

Tsukasa Takayashiki¹  Satoshi Kuboki¹  Ryotaro Eto¹  Masayuki Ohtsuka¹  Satoshi Tomizawa¹  Shigetsugu Takano¹ 

[1] Department of General Surgery, Graduate School of Medicine, Chiba University, 260-8677, Chiba, Japan;

关键词: SEMA3C;    Pancreatic cancer;    Peritoneal dissemination;    Chemoresistance;    Cancer stemness;   

DOI  :  10.1186/s12935-023-03008-3

 received in 2023-06-01, accepted in 2023-07-27,  发布年份 2023

来源: Springer

【 摘 要 】

PurposeSemaphorins, axon guidance cues in neuronal network formation, have been implicated in cancer progression. We previously identified semaphorin 3 C (SEMA3C) as a secreted protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). We, therefore, hypothesized that SEMA3C supports PDAC progression. In this study, we aimed to investigate the clinical features of SEMA3C, especially its association with chemo-resistance and peritoneal dissemination.MethodsIn resected PDAC tissues, we assessed the relationship between SEMA3C expression and clinicopathological features by immunohistochemistry. In vitro studies, we have shown invasion assay, pancreatosphere formation assay, colony formation assay, cytotoxicity assay, and activation of SEMA3C downstream targets (c-Met, Akt, mTOR). In vivo, we performed a preclinical trial to confirm the efficacy of SEMA3C shRNA knockdown and Gemcitabine and nab-Paclitaxel (GnP) in an orthotopic transplantation mouse model and in peritoneal dissemination mouse model.ResultsIn resected PDAC tissues, SEMA3C expression correlated with invasion and peritoneal dissemination after surgery. SEMA3C promoted cell invasion, self-renewal, and colony formation in vitro. We further demonstrated that SEMA3C knockdown increased Gem-induced cytotoxicity by suppressing the activation of the Akt/mTOR pathway via the c-Met receptor. Combination therapy with SEMA3C knockdown and GnP reduced tumor growth and peritoneal dissemination.ConclusionsSEMA3C enhances peritoneal dissemination by regulating putative cancer stemness and Gem resistance and activates phosphorylation of the Akt/mTOR pathway via c-Met. Our findings provide a new avenue for therapeutic strategies in regulating peritoneal dissemination during PDAC progression.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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