2. Academic Validation
  3. Tumor-associated macrophage-induced circMRCKα encodes a peptide to promote glycolysis and progression in hepatocellular carcinoma

Tumor-associated macrophage-induced circMRCKα encodes a peptide to promote glycolysis and progression in hepatocellular carcinoma

  • Cancer Lett. 2024 Jun 1:591:216872. doi: 10.1016/j.canlet.2024.216872.
Songyang Yu 1,  Sheng Su 2,  Pengcheng Wang 3,  Jia Li 4,  Changzhou Chen 5,  Haoyang Xin 6,  Yu Gong 7,  Hezhi Wang 8,  Xinming Ye 9,  Li Mao 10,  Zhengjun Zhou 11,  Shaolai Zhou 12,  Zhiqiang Hu 13,  Xiaowu Huang 14
Affiliations

Affiliations

  • 1 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: dr_ysy@126.com.
  • 2 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: 1425889007@qq.com.
  • 3 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: wangpengcheng39@163.com.
  • 4 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: 845538331@qq.com.
  • 5 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: czchen21@m.fudan.edu.cn.
  • 6 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: hyxin2012@qq.com.
  • 7 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: gong.yu@zs-hospital.sh.cn.
  • 8 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: 22211210055@m.fudan.edu.cn.
  • 9 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: 2211210055@m.fudan.edu.cn.
  • 10 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: sysuncml@163.com.
  • 11 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China. Electronic address: zhouzhengjun1221@126.com.
  • 12 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. Electronic address: zhoushaolai99@sina.com.
  • 13 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. Electronic address: huzhiqiang924@sina.com.
  • 14 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Clinical Center for Biotherapy, Zhongshan Hospital/Zhongshan Hospital (Xiamen), Fudan University, Shanghai/Xiamen, 200032/361015, China. Electronic address: huang.xiaowu@zs-hospital.sh.cn.
PMID: 38642609 DOI: 10.1016/j.canlet.2024.216872
Abstract

The tumor-associated macrophages (TAMs) play multifaceted roles in the progression of hepatocellular carcinoma (HCC). However, the involvement of circular RNAs in the interplay between TAMs and HCC remains unclear. Based on Transwell co-culturing and circular RNA Sequencing, this study revealed that TAMs enhanced tumor glycolysis and progression by upregulating circMRCKα in HCC cells. Patients with HCC who exhibited elevated circMRCKα levels presented significantly reduced overall survival and greater cumulative recurrence. Notably, we identified a novel functional peptide of 227 Amino acids named circMRCKα-227aa, encoded by circMRCKα. Mechanistically, circMRCKα-227aa bound to USP22 and enhanced its protein level to obstruct HIF-1α degradation via the ubiquitin-proteasome pathway, thereby augmenting HCC glycolysis and progression. In clinical HCC samples, a positive correlation was observed between the expression of circMRCKα and the number of infiltrating CD68+ TAMs and expression of USP22. Furthermore, circMRCKα emerged as an independent prognostic risk factor both individually and in conjunction with CD68+ TAMs and USP22. This study illustrated that circMRCKα-227aa, a novel TAM-induced peptide, promotes tumor glycolysis and progression via USP22 binding and HIF-1α upregulation, suggesting that circMRCKα and TAMs could be combined as therapeutic targets in HCC.

Keywords

Circular RNA; Glycolysis; Hepatocellular carcinoma; Tumor-associated macrophages.

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