TACE responser NDRG1 acts as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC

Bufu Tang; Yajie Wang; Jinyu Zhu; Jingjing Song; Shiji Fang; Qiaoyou Weng; Yang Yang; Jianfei Tu; Zhongwei Zhao; Minjiang Chen; Min Xu; Weiqian Chen; Jiansong Ji

doi:10.1186/s12575-023-00199-x

TACE responser NDRG1 acts as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC

Biol Proced Online. 2023 May 19;25(1):13. doi: 10.1186/s12575-023-00199-x.

Authors

Bufu Tang^#^{1

2}, Yajie Wang^#^{1

3}, Jinyu Zhu^#^{1

4}, Jingjing Song^{1

3}, Shiji Fang^{1

3}, Qiaoyou Weng^{1

3}, Yang Yang^{1

3}, Jianfei Tu^{1

3}, Zhongwei Zhao^{1

3}, Minjiang Chen^{1

3}, Min Xu^{1

3}, Weiqian Chen^{5

6}, Jiansong Ji^{7

8}

Affiliations

¹ Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China.
² Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310058, China.
³ Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
⁴ Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China. ls2119088@126.com.
⁶ Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. ls2119088@126.com.
⁷ Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China. jijiansong@zju.edu.cn.
⁸ Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. jijiansong@zju.edu.cn.

^# Contributed equally.

Abstract

Background: The treatment efficacy of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) varies widely between individuals. The aim of this study was to identify subtype landscapes and responser related to TACE, and further clarify the regulatory effect and corresponding mechanism of NDRG1 on HCC tumorgenesis and metastasis.

Methods: The principal component analysis (PCA) algorithm was used to construct a TACE response scoring (TRscore) system. The random forest algorithm was applied to identify the TACE response-related core gene NDRG1 of HCC, and its role in the prognosis of HCC was explored. The role of NDRG1 in the progression and metastasis of HCC and functional mechanism were confirmed using several experimental methods.

Results: Based on the GSE14520 and GSE104580 cohorts, we identified 2 TACE response-related molecular subtypes for HCC with significant differences in clinical features, and the TACE prognosis of Cluster A was significantly better than that of Cluster B (p < 0.0001). We then established the TRscore system and found that the low TRscore group showed a higher probability of survival and a lower rate of recurrence than the high TRscore group (p < 0.05) in both the HCC and TACE-treated HCC cohorts within the GSE14520 cohort. NDRG1 was determined to be the the hub gene associated with the TACE response of HCC and its high expression suggested a poor prognosis. Furthermore, The suppression of NDRG1 konckdown in tumorgenesis and metastasis of HCC was clarified in both vivo and vitro, which was importantly achieved through inducing ferroptosis in HCC cells, especially contributing to RLS3-induced ferroptosis.

Conclusion: The constructed TACE response-related molecular subtypes and TRscores can specifically and accurately predict TACE prognosis for HCC. In addition, the TACE response-related hub gene NDRG1 may act as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC, which laid a new foundation for the development of new potential targeted therapy strategies to improve disease prognosis in HCC patients.

Keywords: Hepatocellular carcinoma (HCC); Immunotherapy; NDRG1; Prognosis; Transarterial chemoembolization (TACE).