Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma

Chun-Ming Ho; Kuen-Tyng Lin; Roger Shen; De-Leung Gu; Szu-Shuo Lee; Wen-Hui Su; Yuh-Shan Jou

doi:10.1016/j.csbj.2022.04.008

Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma

Comput Struct Biotechnol J. 2022 Apr 9:20:1752-1763. doi: 10.1016/j.csbj.2022.04.008. eCollection 2022.

Authors

Chun-Ming Ho^{1

2

3}, Kuen-Tyng Lin¹, Roger Shen¹, De-Leung Gu¹, Szu-Shuo Lee^{1

4}, Wen-Hui Su^{5

6}, Yuh-Shan Jou^{1

2

4}

Affiliations

¹ Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
² Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
³ Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 300, Taiwan.
⁴ Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 115, Taiwan.
⁵ Department of Biomedical Sciences, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan.
⁶ Department of Otolaryngology, Chang Gung Memorial Hospital, Linkou, 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan.

Abstract

With the increasing incidence and mortality of human hepatocellular carcinoma (HCC) worldwide, revealing innovative targets to improve therapeutic strategies is crucial for prolonging the lives of patients. To identify innovative targets, we conducted a comprehensive comparative transcriptome analysis of 5,410 human HCCs and 974 mouse liver cancers to identify concordantly expressed genes associated with patient survival. Among the 664 identified prognostic comparative HCC (pcHCC) genes, upregulated pcHCC genes were associated with prognostic clinical features, including large tumor size, vascular invasion and late HCC stages. Interestingly, after validating HCC patient prognoses in multiple independent datasets, we matched the 664 aberrant pcHCC genes with the sorafenib-altered genes in TCGA_LIHC patients and found these 664 pcHCC genes were enriched in sorafenib-related functions, such as downregulated xenobiotic and lipid metabolism and upregulated cell proliferation. Therapeutic agents targeting aberrant pcHCC genes presented divergent molecular mechanisms, including suppression of sorafenib-unrelated oncogenic pathways, induction of sorafenib-unrelated ferroptosis, and modulation of sorafenib transportation and metabolism, to potentiate sorafenib therapeutic effects in HCC combination therapy. Moreover, the pcHCC genes NCAPG and CENPW, which have not been targeted in combination with sorafenib treatment, were knocked down and combined with sorafenib treatment, which reduced HCC cell viability based on disruption to the p38/STAT3 axis, thereby hypersensitizing HCC cells. Together, our results provide important resources and reveal that 664 pcHCC genes represent innovative targets suitable for developing therapeutic strategies in combination with sorafenib based on the divergent synergistic mechanisms for HCC tumor suppression.

Keywords: CENPW; CENPW, Centromere protein W; Comparative genomic analysis; DEG, Differential expression gene; Hepatocellular carcinoma; NCAPG; NCAPG, Non-SMC condensin I complex subunit G; Prognosis; Sorafenib combination therapy; TCGA_LIHC, The Cancer Genome Atlas_Liver Hepatocellular Carcinoma; pcHCC, Prognostic comparative hepatocellular carcinoma.