Connexin43 Promotes the Invasion and Metastasis of Lung Squamous Cell Carcinoma via GJIC-Dependent Ca²⁺/ERK Signaling Activation.

IF 5.7 2区医学 Q1 Medicine

Cancer Science Pub Date : 2025-05-31 DOI:10.1111/cas.70076

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

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引用次数: 0

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 Ca²⁺ transmission and ERK phosphorylation, whereas the addition of Ca²⁺ 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 Ca²⁺/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.

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Connexin43通过gjic依赖性Ca2+/ERK信号激活促进肺鳞状细胞癌的侵袭和转移

肺鳞状细胞癌（LUSC）是一种极具转移性的癌症，治疗方法有限，预后差。Connexin43 （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并与肿瘤发生正相关，但其在LUSC中的作用尚不清楚。在本研究中，我们发现Cx43在LUSC组织中比匹配的正常肺组织高表达（n = 103），并且与预后呈负相关。通过三维球体细胞侵袭实验、zCDX（斑马鱼细胞系来源的异种移植）和原位肺癌异种移植模型，我们进一步发现Cx43通过形成GJIC促进LUSC的侵袭和迁移。Cx43的敲低降低了Ca2+的传递和ERK的磷酸化，而Ca2+的加入增强了ERK的磷酸化，促进了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磷酸化和LUSC细胞的侵袭和迁移。机制上，Cx43通过缝隙连接胞内通讯（gap junctional intracellular communication， GJIC）激活Ca2+/ERK信号通路，促进LUSC的侵袭和转移。我们的研究结果为LUSC侵袭和迁移提供了新的机制，并为解决这种疾病的新治疗策略提供了概念证明。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Science ONCOLOGY-

CiteScore

9.90

自引率

3.50%

发文量

406

审稿时长

17 weeks

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.