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连接蛋白43通过依赖缝隙连接细胞间通讯的钙/细胞外信号调节激酶信号激活促进肺鳞状细胞癌的侵袭和转移。

Connexin43 Promotes the Invasion and Metastasis of Lung Squamous Cell Carcinoma via GJIC-Dependent Ca/ERK Signaling Activation.

作者信息

Mo Xiaocheng, He Jingchuan, Shen Xiaoju, Li Changsheng, Mo Xiaoxiang, Liang Kai, He Liangjun, Li Tingting, Pan Xiaoqin, Cao Sisi, Mao Naiquan, Xing Shangping, Chen Zhiquan, Luo Zhuo, Yang Jie

机构信息

Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, Guangxi, People's Republic of China.

Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

出版信息

Cancer Sci. 2025 Aug;116(8):2086-2100. doi: 10.1111/cas.70076. Epub 2025 May 31.

DOI:10.1111/cas.70076
PMID:40449992
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12317405/
Abstract

Lung squamous cell carcinoma (LUSC) is an extremely metastatic cancer with limited available treatment and poor outcomes. Connexin43 (Cx43) is frequently overactivated and positively correlated with tumorigenesis in many cancers, including breast cancer and lung adenocarcinoma, but its role in LUSC remains elusive. In this study, we demonstrated that Cx43 was highly expressed in LUSC tissues as compared to matching normal lung tissues (n = 103) and negatively related to prognosis. Through the 3D spheroid cell invasion assay, zCDX (zebrafish cell line-derived xenograft), and orthotopic lung cancer xenograft model, we further revealed that Cx43 promotes LUSC invasion and migration via forming GJIC. Knockdown of Cx43 reduced the Ca transmission and ERK phosphorylation, whereas the addition of Ca enhanced ERK phosphorylation and promoted LUSC invasion and migration. Furthermore, verapamil (40 μM and 80 μM), a calcium channel inhibitor, significantly inhibited ERK phosphorylation as well as the invasion and migration of LUSC cells. Mechanistically, Cx43 promoted the invasion and metastasis of LUSC via activating the Ca/ERK signaling pathway by gap junctional intracellular communication (GJIC). Our findings provide a novel mechanism insight for LUSC invasion and migration and a proof of concept for a new therapeutic strategy to tackle this disease.

摘要

肺鳞状细胞癌（LUSC）是一种具有极高转移性的癌症，可用治疗手段有限，预后较差。连接蛋白43（Cx43）在包括乳腺癌和肺腺癌在内的许多癌症中经常过度激活，且与肿瘤发生呈正相关，但其在LUSC中的作用仍不清楚。在本研究中，我们证明与配对的正常肺组织（n = 103）相比，Cx43在LUSC组织中高表达，且与预后呈负相关。通过三维球体细胞侵袭试验、斑马鱼细胞系衍生异种移植（zCDX）和原位肺癌异种移植模型，我们进一步揭示Cx43通过形成缝隙连接细胞间通讯（GJIC）促进LUSC的侵袭和迁移。敲低Cx43可降低钙传递和ERK磷酸化，而添加钙可增强ERK磷酸化并促进LUSC的侵袭和迁移。此外，钙通道抑制剂维拉帕米（40 μM和80 μM）显著抑制ERK磷酸化以及LUSC细胞的侵袭和迁移。机制上，Cx43通过缝隙连接细胞间通讯（GJIC）激活钙/ERK信号通路促进LUSC的侵袭和转移。我们的研究结果为LUSC的侵袭和迁移提供了新的机制见解，并为治疗该疾病的新治疗策略提供了概念验证。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/004d8fc4b208/CAS-116-2086-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/b785feda8ff6/CAS-116-2086-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/30c9c138ff0e/CAS-116-2086-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/69bca144096d/CAS-116-2086-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/4ed3e9a68696/CAS-116-2086-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/a1a43aba88c3/CAS-116-2086-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/004d8fc4b208/CAS-116-2086-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/b785feda8ff6/CAS-116-2086-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/30c9c138ff0e/CAS-116-2086-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/69bca144096d/CAS-116-2086-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/4ed3e9a68696/CAS-116-2086-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/a1a43aba88c3/CAS-116-2086-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63b0/12317405/004d8fc4b208/CAS-116-2086-g006.jpg

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本文引用的文献

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Rab32 promotes glioblastoma migration and invasion via regulation of ERK/Drp1-mediated mitochondrial fission.Rab32 通过调控 ERK/Drp1 介导的线粒体分裂促进胶质母细胞瘤迁移和侵袭。
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Integrated bioinformatics analyses identifying key transcriptomes correlated with prognosis and immune infiltrations in lung squamous cell carcinoma.
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Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca 2+ -dependent gap junction intercellular communication.连接蛋白 43 修饰的骨髓基质细胞通过 Ca 2+ 依赖的缝隙连接细胞间通讯逆转 K562 细胞对伊马替尼的耐药性。
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