Research Paper Volume 15, Issue 10 pp 4304—4318

Integrated network findings reveal ubiquitin-specific protease 44 overexpression suppresses tumorigenicity of liver cancer

Huanhuan Zhou1, *, , Lu Yang1, *, , Xiao Lin3, , Ting Fung Chan4, , Nikki Pui-Yue Lee5, , William Ka Fai Tse6, , Xing Zhang1,2, &, , Rong Li1,2, , Keng Po Lai1,2, ,

  • 1 Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin, Guangxi, PR China
  • 2 Department of Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, PR China
  • 3 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  • 4 School of Life Sciences, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong SAR, China
  • 5 Department of Surgery, University of Hong Kong, Hong Kong SAR, China
  • 6 Center for Promotion of International Education and Research, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
* Equal contribution

Received: February 27, 2023       Accepted: May 9, 2023       Published: May 18, 2023
How to Cite

Copyright: © 2023 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related deaths worldwide. HCC is a multistep disease marked by various signaling alterations. A better understanding of the new molecular drivers of HCC could therefore provide an opportunity to develop effective diagnostic and therapeutic targets. Ubiquitin-specific protease 44 (USP44), a member of the cysteine protease family, has been reported to play a role in many cancer types. However, its contribution to HCC development remains unknown. In the present study, we observed suppression of USP44 expression in HCC tissue. Clinicopathologic analysis further showed that low USP44 expression correlated with poorer survival and a later tumor stage in HCC, suggesting that USP44 could be a predictor of poor prognosis in patients with HCC. Gain-of-function analysis in vitro demonstrated the importance of USP44 in HCC cell growth and G0/G1 cell cycle arrest. To investigate the downstream targets of USP44 and the molecular mechanisms underlying its regulation of cell proliferation in HCC, we conducted a comparative transcriptomic analysis and identified a cluster of proliferation-related genes, including CCND2, CCNG2, and SMC3. Ingenuity Pathway Analysis further delineated the gene networks controlled by USP44 through the regulation of membrane proteins and receptors, enzymes, transcriptional factors, and cyclins involved in the control of cell proliferation, metastasis, and apoptosis in HCC. To summarize, our results highlight, for the first time, the tumor-suppression role of USP44 in HCC and suggest a new prognostic biomarker in this disease.


HCC: Hepatocellular carcinoma; USP44: Ubiquitin-specific protease 44; CCND2: Cyclin D2; CCNG2: cyclin G2; SMC3: chromosomes protein 3; RT-PCR: quantitative real-time PCR; CCK-8: Cell Counting Kit-8; DEGs: differentially expressed genes; IPA: Ingenuity Pathway Analysis; T: tumors; NT: nontumoral liver tissue; FZD2: frizzled family protein 2; ROCK2: rho-associated protein kinase 2.