Aberrant activation of a miR-101-UBE2D1 axis contributes to the advanced progression and chemotherapy sensitivity in human hepatocellular carcinoma

Xiuli Mu; Yuchen Wei; Xin Fan; Rui Zhang; Wenjin Xi; Guoxu Zheng; An-Gang Yang

doi:10.1038/s41420-024-02193-y

Aberrant activation of a miR-101-UBE2D1 axis contributes to the advanced progression and chemotherapy sensitivity in human hepatocellular carcinoma

Cell Death Discov. 2024 Oct 1;10(1):422. doi: 10.1038/s41420-024-02193-y.

Authors

Xiuli Mu^#¹, Yuchen Wei^#^{1

2}, Xin Fan^{1

3}, Rui Zhang^{1

2}, Wenjin Xi¹, Guoxu Zheng⁴, An-Gang Yang⁵

Affiliations

¹ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
² State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
³ Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
⁴ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
⁵ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].

^# Contributed equally.

Abstract

Chemotherapeutic drugs, such as cisplatin (cis-dichlorodiamineplatinum [II], cDDP) and 5-fluorouracil (5Fu), are widely used in transarterial chemoembolization (TACE), which is a standard therapy for patients with hepatocellular carcinoma (HCC). Chemoresistance is a major cause of TACE treatment failure in HCC patients. Our previous studies have identified the expression levels of miR-101 responsive genes, such as EED, EZH2, STMN1 and JUNB, exhibit significant correlation with the occurrence and progression of HCC, while the role of miR-101 responsive gene signatures in the chemoresistance of HCC treatment remains unclear. In this study, we identified ubiquitin-coupled enzyme E2D1 (UBE2D1) as a crucial regulatory factor in the chemoresistance of HCC, which is a direct target of miR-101 and exhibits significant correlation with miR-101-responsive gene signatures. The bioinformatics analysis showed the expression of UBE2D1 was significantly increased in HCC tissues and was closely correlated with the poor prognosis. In addition, we analyzed the role of miR-101/UBE2D1 axis in regulating chemo-sensitive of HCC cells. Our results showed that miR-101 increases the DNA damage and apoptosis of HCC cells by inhibiting the expression of UBE2D1, which in turn increases the sensitivity of HCC cells to cDDP and 5Fu both in vitro and in vivo. Therefore, simultaneous assessment of miR-101 and UBE2D1 expression levels might provide an effective approach in preselecting HCC patients with survival benefit from TACE treatment. Moreover, further elucidation of the underlying molecular mechanisms of the miR-101/UBE2D1 axis could provide novel insight for targeted therapy of HCC.