Department of Gastroenterology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China.
Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, China.
Dig Dis Sci. 2022 Jan;67(1):134-145. doi: 10.1007/s10620-021-06847-0. Epub 2021 Feb 2.
Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. TGFβ1 has been the mostly accepted factor to fuel normal fibroblasts transformation into CAFs. Ca/calmodulin-dependent protein kinase II (CaMKII) is thought to play an important role in fibroblasts activation induced by TGFβ1. The aim of this study is to investigate the potential role of CaMKII in TGFβ1-induced fibroblasts activation and CAF-like differentiation. Cross talk between CaMKII-dependent fibroblasts and colon cancer in colon cancer progression also was addressed RESULTS: Immunostaining demonstrated that in colon cancer stroma, CaMKII overexpressed in stromal CAFs. In vitro, TGFβ1 increased CAF markers expression in human colon fibroblasts CCD-18Co, but not in CaMKII depletion fibroblasts. CaMKII knockdown by CaMKII shRNA significantly inhibited TGFβ1-induced fibroblasts activation and CAF-like differentiation. Smad3, AKT, and MAPK were targeted in TGFβ1-CaMKII-mediated pathway. Human colon cancer cell line HCT-116 activated fibroblasts directly, whereas CaMKII depletion dragged CCD-18Co fibroblasts undergoing CAF-associated trans-differentiation. Furthermore, increased proliferation, migration, and invasion of colon cancer cells were stimulated when co-cultured with normal fibroblasts, but not with CaMKII depletion fibroblasts.
These findings provide evidence that CaMKII is a critical mediator in TGFβ1-induced fibroblasts activation and is involved in the cross talk with colon cancer cells. CaMKII is a potentially effective target for future treatment of colon cancer.
癌症相关成纤维细胞（CAFs）作为肿瘤基质中激活的成纤维细胞，是肿瘤进展的重要修饰物。TGFβ1 已被广泛接受为促使正常成纤维细胞转化为 CAFs 的因素。钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）被认为在 TGFβ1 诱导的成纤维细胞激活和 CAF 样分化中发挥重要作用。本研究旨在探讨 CaMKII 在 TGFβ1 诱导的成纤维细胞激活和 CAF 样分化中的潜在作用。还探讨了 CaMKII 依赖性成纤维细胞与结肠癌在结肠癌进展中的相互作用。结果：免疫组化显示在结肠癌基质中，CaMKII 在基质 CAFs 中过表达。在体外，TGFβ1 增加了人结肠成纤维细胞 CCD-18Co 的 CAF 标志物表达，但在 CaMKII 耗竭的成纤维细胞中没有。CaMKII shRNA 敲低 CaMKII 显著抑制 TGFβ1 诱导的成纤维细胞激活和 CAF 样分化。Smad3、AKT 和 MAPK 是 TGFβ1-CaMKII 介导途径中的靶点。人结肠癌细胞系 HCT-116 直接激活成纤维细胞，而 CaMKII 耗竭使 CCD-18Co 成纤维细胞经历 CAF 相关转分化。此外，当与正常成纤维细胞共培养时，会刺激结肠癌细胞增殖、迁移和侵袭增加，但与 CaMKII 耗竭的成纤维细胞共培养时不会。结论：这些发现为 CaMKII 是 TGFβ1 诱导的成纤维细胞激活的关键介质，并参与与结肠癌细胞的相互作用提供了证据。CaMKII 是未来结肠癌治疗的一个潜在有效靶点。
