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CaMKII Mediates TGFβ1-Induced Fibroblasts Activation and Its Cross Talk with Colon Cancer Cells

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Abstract

Introduction

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. Ca2+/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.

Conclusions

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.

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Abbreviations

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

TGFβ1:

Transforming growth factor β1

CAF:

Cancer-associated fibroblast

CRC:

Colorectal cancer

α-SMA:

α-Smooth muscle actin

FAP:

Fibroblast activation protein

FN:

Fibronectin

PDGF:

Platelet-derived growth factor

EGF:

Epidermal growth factor

FGF:

Fibroblast growth factors

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Acknowledgments

This work was supported by National Natural Science Foundation of China (81302131), Medical Scientific Research Foundation of Guangdong Province (A2015297), and Shenzhen Science and Technology Project (JCYJ20150402152130164).

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Authors and Affiliations

  1. Department of Gastroenterology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China

    Wei Chen, Juan Su, Jian Kang, Yijuan Ding, Jun Zhang, Hesheng Luo & Ping An

  2. Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, China

    Wei Chen, Juan Su, Jian Kang, Yijuan Ding, Jun Zhang & Ping An

  3. Department of Pulmonary Critical Care Medicine, Shenzhen Shekou People’s Hospital, No. 36 the 7th Industry Road, Shekou, Shenzhen, 518067, China

    Yanwei Chen

  4. Department of Cardiology, Shenzhen Nanshan People’s Hospital, Shenzhen, 518102, China

    Wen Ai

  5. Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Ping An

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  1. Wei Chen
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Chen, W., Chen, Y., Su, J. et al. CaMKII Mediates TGFβ1-Induced Fibroblasts Activation and Its Cross Talk with Colon Cancer Cells. Dig Dis Sci 67, 134–145 (2022). https://doi.org/10.1007/s10620-021-06847-0

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  • DOI: https://doi.org/10.1007/s10620-021-06847-0

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