1. Academic Validation
  2. Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis

Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis

  • J Exp Clin Cancer Res. 2022 Feb 22;41(1):73. doi: 10.1186/s13046-022-02286-5.
Hongkun Cai # 1 2 Feng Guo # 1 2 Shuang Wen # 3 Xin Jin 4 Heshui Wu 5 6 Dianyun Ren 7 8
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3 Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
  • 4 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. jinxinunion@hust.edu.cn.
  • 5 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. heshuiwu@hust.edu.cn.
  • 6 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. heshuiwu@hust.edu.cn.
  • 7 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. rendianyun@hust.edu.cn.
  • 8 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. rendianyun@hust.edu.cn.
  • # Contributed equally.
Abstract

Background: Integrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic Cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic Cancer are still unclear.

Methods: The GEPIA database was used to confirm the expression of ITGA2 in pancreatic Cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic Cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test.

Results: The results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic Cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic Cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway.

Conclusions: Taken together, these results indicated that ITGA2 expression could inhibit the activation of the TGF-β signaling pathway in pancreatic Cancer via the TFCP2-SMAD2 axis. Therefore, ITGA2, by effectively enhancing the anti-cancer effects of TGF- β, might be a potential clinical therapeutic target for pancreatic Cancer.

Keywords

Integrin α2; Pancreatic cancer; SMAD2; TGF-β; Transcription factor CP2.

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