Tomizawa Satoshi, Takano Shigetsugu, Eto Ryotaro, Takayashiki Tsukasa, Kuboki Satoshi, Ohtsuka Masayuki
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan.
Cancer Cell Int. 2023 Aug 3;23(1):155. doi: 10.1186/s12935-023-03008-3.
Semaphorins, 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.
In 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.
In 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.
SEMA3C 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.
信号素作为神经网络形成中的轴突导向因子，与癌症进展有关。我们之前鉴定出信号素3C（SEMA3C）是一种在胰腺导管腺癌（PDAC）中过表达的分泌蛋白。因此，我们推测SEMA3C促进PDAC进展。在本研究中，我们旨在探究SEMA3C的临床特征，尤其是其与化疗耐药性和腹膜播散的关系。
在切除的PDAC组织中，我们通过免疫组织化学评估SEMA3C表达与临床病理特征之间的关系。在体外研究中，我们进行了侵袭试验、胰腺球形成试验、集落形成试验、细胞毒性试验以及SEMA3C下游靶点（c-Met、Akt、mTOR）的激活试验。在体内，我们进行了一项临床前试验，以证实SEMA3C短发夹RNA敲低以及吉西他滨和纳米白蛋白结合型紫杉醇（GnP）在原位移植小鼠模型和腹膜播散小鼠模型中的疗效。
在切除的PDAC组织中，SEMA3C表达与术后侵袭和腹膜播散相关。SEMA3C在体外促进细胞侵袭、自我更新和集落形成。我们进一步证明，SEMA3C敲低通过抑制c-Met受体介导的Akt/mTOR途径激活来增加吉西他滨诱导的细胞毒性。SEMA3C敲低与GnP联合治疗可减少肿瘤生长和腹膜播散。
SEMA3C通过调节假定的癌症干性和吉西他滨耐药性增强腹膜播散，并通过c-Met激活Akt/mTOR途径的磷酸化。我们的研究结果为PDAC进展过程中调节腹膜播散的治疗策略提供了新途径。
