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间皮素诱导胰腺癌细胞发生上皮-间质转化、癌症干细胞特性及化疗耐药。

MSLN induced EMT, cancer stem cell traits and chemotherapy resistance of pancreatic cancer cells.

作者信息

Hu Jili, Wang Jia, Guo Xu, Fan Qing, Li Xinming, Li Kai, Wang Zhuoyin, Liang Shuntao, Amin Buhe, Zhang Nengwei, Chen Chaowen, Zhu Bin

机构信息

Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, 450052, China.

出版信息

Heliyon. 2024 Apr 7;10(8):e29210. doi: 10.1016/j.heliyon.2024.e29210. eCollection 2024 Apr 30.

DOI:10.1016/j.heliyon.2024.e29210
PMID:38628720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11019237/
Abstract

Chemoresistance is one of the main reasons for poor prognosis of pancreatic cancer. The effects of mesothelin (MSLN) on chemoresistance in pancreatic cancer are still unclear. We aim to investigate potential roles of MSLN in chemoresistance and its relationship with proliferation, epithelial-mesenchymal transition (EMT) and cancer stemness of pancreatic cancer cells. Human pancreatic cancer cell lines ASPC-1 and Mia PaCa-2 with high and low expression of MSLN, respectively, were selected. The ASPC-1 with MSLN knockout (KO) and Mia PaCa-2 of MSLN overexpression (OE) were generated. The effects of MSLN on cell phenotypes, expression of EMT-related markers, clone formation, tumor sphere formation, and pathologic role of MSLN in tumorigenesis were detected. Sensitivity of tumor cells to gemcitabine was evaluated. The results showed that adhesion, proliferation, migration and invasion were decreased significantly in ASPC-1 with MSLN KO, whereas increased significantly in Mia PaCa-2 with MSLN OE. The size and the number of clones and tumor spheres were decreased in ASPC-1 with MSLN KO, and increased in Mia PaCa-2 with MSLN OE. In xenograft model, tumor volume was decreased (tumor grew slower) in MSLN KO group compared to control group, while increased in MSLN OE group. Mia PaCa-2 with MSLN OE had a higher IC50 of gemcitabine, while ASPC-1 with MSLN KO had a lower IC50. We concluded that MSLN could induce chemoresistance by enhancing migration, invasion, EMT and cancer stem cell traits of pancreatic cancer cells. Targeting MSLN could represent a promising therapeutic strategy for reversing EMT and chemoresistance in pancreatic cancer cells.

摘要

化疗耐药是胰腺癌预后不良的主要原因之一。间皮素（MSLN）对胰腺癌化疗耐药的影响尚不清楚。我们旨在研究MSLN在化疗耐药中的潜在作用及其与胰腺癌细胞增殖、上皮-间质转化（EMT）和癌症干性的关系。分别选择了MSLN高表达和低表达的人胰腺癌细胞系ASPC-1和Mia PaCa-2。构建了MSLN基因敲除（KO）的ASPC-1细胞系和MSLN过表达（OE）的Mia PaCa-2细胞系。检测了MSLN对细胞表型、EMT相关标志物表达、克隆形成、肿瘤球形成的影响以及MSLN在肿瘤发生中的病理作用。评估了肿瘤细胞对吉西他滨的敏感性。结果显示，MSLN基因敲除的ASPC-1细胞的黏附、增殖、迁移和侵袭能力显著降低，而MSLN过表达的Mia PaCa-2细胞的这些能力显著增强。MSLN基因敲除的ASPC-1细胞的克隆和肿瘤球的大小及数量减少，而MSLN过表达的Mia PaCa-2细胞的则增加。在异种移植模型中，与对照组相比，MSLN基因敲除组的肿瘤体积减小（肿瘤生长较慢），而MSLN过表达组的肿瘤体积增大。MSLN过表达的Mia PaCa-2细胞对吉西他滨的半数抑制浓度（IC50）较高，而MSLN基因敲除的ASPC-1细胞的IC50较低。我们得出结论，MSLN可通过增强胰腺癌细胞的迁移、侵袭、EMT和癌症干细胞特性来诱导化疗耐药。靶向MSLN可能是一种有前景的治疗策略，可逆转胰腺癌细胞的EMT和化疗耐药。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df11/11019237/abe794be69d5/mmcfigs11.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df11/11019237/abe794be69d5/mmcfigs11.jpg

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