2. Academic Validation
  3. Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma

Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma

  • Exp Cell Res. 2024 Mar 1;436(1):113956. doi: 10.1016/j.yexcr.2024.113956.
He-Ming Zhou 1,  Da-Hong Chen 1,  Wen-Jing Diao 1,  Ya-Fei Wu 1,  Ji-Gang Zhang 2,  Lin Zhong 3,  Zhong-Yi Jiang 3,  Xue Zhang 4,  Gao-Lin Liu 4,  Qin Li 5
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, PR China.
  • 2 Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, PR China.
  • 3 Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, PR China.
  • 4 Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, PR China; Shanghai Eye Diseases Prevention & Treatment Center / Shanghai Eye Hospital, Shanghai, 200040, PR China.
  • 5 Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, PR China; Shanghai Eye Diseases Prevention & Treatment Center / Shanghai Eye Hospital, Shanghai, 200040, PR China. Electronic address: [email protected].
PMID: 38341081 DOI: 10.1016/j.yexcr.2024.113956
Abstract

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and Cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.

Keywords

Drug resistance; HCC; Regorafenib; RhoA; Stemness.

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