2. Academic Validation
  3. AFP deletion leads to anti-tumorigenic but pro-metastatic roles in liver cancers with concomitant CTNNB1 mutations

AFP deletion leads to anti-tumorigenic but pro-metastatic roles in liver cancers with concomitant CTNNB1 mutations

  • Cancer Lett. 2023 May 20;216240. doi: 10.1016/j.canlet.2023.216240.
Ye Xu 1,  Xuefeng Zhang 2,  Ruitian Zhang 1,  Yuening Sun 1,  Jian Liu 1,  Chengju Luo 1,  Junyi Yang 1,  Weiming Fang 1,  Qinglong Guo 3,  Libin Wei 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China; Jiangsu Tripod Preclinincal Research Laboratories Co., Ltd., No. 9 Xinglong Road, Nanjing, 211800, People's Republic of China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address: qinglongguo@hotmail.com.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address: wlbiws_1986@aliyun.com.
PMID: 37217071 DOI: 10.1016/j.canlet.2023.216240
Abstract

HCC remains one of the most prevalent and deadliest cancers. Serum AFP level is a biomarker for clinical diagnosis of HCC, instead the contribution of AFP to HCC development is clearly highly complex. Here, we discussed the effect of AFP deletion in the tumorigenesis and progression of HCC. AFP deletion in HepG2 cells inhibited the cell proliferation by inactivating PI3K/Akt signaling. Surprisingly, AFP KO HepG2 cells appeared the increasing metastatic capacity and EMT phenotype, which was attributed to the activation of WNT5A/β-catenin signal. Further studies revealed that the activating mutations of CTNNB1 was closely related with the unconventional pro-metastatic roles of AFP deletion. Consistently, the results of DEN/CCl4-induced HCC mouse model also suggested that AFP knockout suppressed the growth of HCC primary tumors, but promoted lung metastasis. Despite the discordant effect of AFP deletion in HCC progression, a drug candidate named OA showed the potent suppression of HCC tumor growth by interrupting AFP-PTEN interaction, and, importantly, reduced the lung metastasis of HCC via angiogenesis suppression. Thus, this study demonstrates an unconventional effect of AFP in HCC progression, and suggests a potent candidate strategy for HCC therapy.

Keywords

Alpha fetoprotein; CRISPR/Cas9 technology; Epithelial mesenchymal transition; Hepatocellular carcinoma; Oroxylin a.

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