Cancer/testis-45A1 promotes cervical cancer cell tumorigenesis and drug resistance by activating oncogenic SRC and downstream signaling pathways

Cell Oncol (Dordr). 2023 Nov 4. doi: 10.1007/s13402-023-00891-w.

Mei Meng ^# ¹ ² ³ ⁴ ⁵, Yan Guo ⁶, Yu Chen ^# ¹, Xu Li ^# ¹, Bin Zhang ⁷, Zhijia Xie ⁸, Juntao Liu ¹, Zhe Zhao ⁹, Yuxi Liu ¹, Tong Zhang ¹, Yingnan Qiao ¹, Bingxue Shang ¹⁰ ¹¹, Quansheng Zhou ¹² ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu, 215123, People's Republic of China.
2 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China.
3 National Clinical Research Center for Hematologic Diseases, The Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China.
4 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China.
5 The Ninth Affiliated Hospital, Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China.
6 Department of Gynecology and Obstetrics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People's Republic of China. guoyansdfyy@163.com.
7 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, People's Republic of China.
8 Department of Obstetrics and Gynecology, The Ninth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China.
9 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, Jiangsu, China.
10 Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. bingchengliren@163.com.
11 Suzhou Institute of Systems Medicine, Suzhou, China. bingchengliren@163.com.
12 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu, 215123, People's Republic of China. zhouqs@suda.edu.cn.
13 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China. zhouqs@suda.edu.cn.
14 National Clinical Research Center for Hematologic Diseases, The Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China. zhouqs@suda.edu.cn.
15 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China. zhouqs@suda.edu.cn.
16 The Ninth Affiliated Hospital, Soochow University, Suzhou, Jiangsu, 215123, People's Republic of China. zhouqs@suda.edu.cn.
# Contributed equally.

PMID: 37924456 DOI: 10.1007/s13402-023-00891-w

Abstract

Background: Cancer/testis antigen-45A1 (CT45A1) is overexpressed in various types of Cancer but is not expressed in healthy women. The role of CT45A1 in cervical Cancer has not yet been described in the literature.

Purpose: The aim of this research was to study the role of CT45A1 in cervical Cancer progression and drug resistance, elucidate the mechanisms underlying CT45A1-mediated tumorigenesis and investigate CT45A1 as a biomarker for cervical Cancer diagnosis, prognostic prediction, and targeted therapy.

Methods: The CT45A1 levels in the tumors from cervical Cancer patients were measured using immunohistochemical staining. The role and mechanisms underlying CT45A1-mediated cervical Cancer cell tumor growth, invasion, and drug resistance were studied using xenograft mice, cervical Cancer cells, immunohistochemistry, RNA-seq, real-time qPCR, Chromatin immunoprecipitation and Western blotting.

Results: CT45A1 levels were notably high in the tumor tissues of human cervical Cancer patients compared to the paracancerous tissues (p < 0.001). Overexpression of CT45A1 was closely associated with poor prognosis in cervical Cancer patients. CT45A1 promoted cervical Cancer cell tumor growth, invasion, neovascularization, and drug resistance. Mechanistically, CT45A1 promoted the expression of 128 pro-tumorigenic genes and concurrently activated key signaling pathways, including the oncogenic Src, ERK, CREB, and YAP/TAZ signaling pathways. Furthermore, CT45A1-mediated tumorigenesis and drug resistance were markedly inhibited by the small molecule lycorine.

Conclusion: CT45A1 promotes cervical Cancer cell tumorigenesis, neovascularization, and drug resistance by activating oncogenic Src and downstream tumorigenic signaling pathways. These findings provide new insight into the pathogenesis of cervical Cancer and offer a new platform for the development of novel therapeutics against cervical Cancer.

Keywords

Biomarker; CT45A1; Cancer therapy; Cervical cancer; Lycorine; Tumorigenesis.

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