2. Academic Validation
  3. TFCP2L1 drives stemness and enhances their resistance to Sorafenib treatment by modulating the NANOG/STAT3 pathway in hepatocellular carcinoma

TFCP2L1 drives stemness and enhances their resistance to Sorafenib treatment by modulating the NANOG/STAT3 pathway in hepatocellular carcinoma

  • Oncogenesis. 2024 Sep 12;13(1):33. doi: 10.1038/s41389-024-00534-1.
Dongbo Qiu # 1 2 3,  Tiantian Wang # 4,  Yi Xiong # 3,  Kun Li 3,  Xiusheng Qiu 1,  Yuan Feng 5,  Qinghai Lian 1,  Yunfei Qin 3,  Kunpeng Liu 6,  Qi Zhang 7 8,  Changchang Jia 9 10
Affiliations

Affiliations

  • 1 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Cell-gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Medical Oncology; the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 5 Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 6 Medical college of Guangxi University, Nanning, Guangxi, China. liukp@gxu.edu.cn.
  • 7 Cell-gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. zhangq27@mail.sysu.edu.cn.
  • 8 Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. zhangq27@mail.sysu.edu.cn.
  • 9 Cell-gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. jiachch3@mail.sysu.edu.cn.
  • 10 Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. jiachch3@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39266516 DOI: 10.1038/s41389-024-00534-1
Abstract

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver Cancer Stem Cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1's essential role in liver CSCs' function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1's active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1's pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.

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