Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma
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 analys...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-01-01
|
| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022001258 |
| _version_ | 1828088005659721728 |
|---|---|
| author | Chun-Ming Ho Kuen-Tyng Lin Roger Shen De-Leung Gu Szu-Shuo Lee Wen-Hui Su Yuh-Shan Jou |
| author_facet | Chun-Ming Ho Kuen-Tyng Lin Roger Shen De-Leung Gu Szu-Shuo Lee Wen-Hui Su Yuh-Shan Jou |
| author_sort | Chun-Ming Ho |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:20:02Z |
| format | Article |
| id | doaj.art-e4d27b2ec005464a8f61097ba9184026 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:20:02Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-e4d27b2ec005464a8f61097ba91840262022-12-24T04:52:01ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012017521763Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinomaChun-Ming Ho0Kuen-Tyng Lin1Roger Shen2De-Leung Gu3Szu-Shuo Lee4Wen-Hui Su5Yuh-Shan Jou6Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 300, TaiwanInstitute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, TaiwanInstitute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, TaiwanInstitute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, TaiwanInstitute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 115, TaiwanDepartment 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; Department of Otolaryngology, Chang Gung Memorial Hospital, Linkou, 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan; Corresponding authors.Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 115, Taiwan; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2001037022001258Comparative genomic analysisHepatocellular carcinomaPrognosisSorafenib combination therapyCENPWNCAPG |
| spellingShingle | Chun-Ming Ho Kuen-Tyng Lin Roger Shen De-Leung Gu Szu-Shuo Lee Wen-Hui Su Yuh-Shan Jou Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma Computational and Structural Biotechnology Journal Comparative genomic analysis Hepatocellular carcinoma Prognosis Sorafenib combination therapy CENPW NCAPG |
| title | Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma |
| title_full | Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma |
| title_fullStr | Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma |
| title_full_unstemmed | Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma |
| title_short | Prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma |
| title_sort | prognostic comparative genes predict targets for sorafenib combination therapies in hepatocellular carcinoma |
| topic | Comparative genomic analysis Hepatocellular carcinoma Prognosis Sorafenib combination therapy CENPW NCAPG |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022001258 |
| work_keys_str_mv | AT chunmingho prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma AT kuentynglin prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma AT rogershen prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma AT deleunggu prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma AT szushuolee prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma AT wenhuisu prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma AT yuhshanjou prognosticcomparativegenespredicttargetsforsorafenibcombinationtherapiesinhepatocellularcarcinoma |