EFNA3 is a prognostic biomarker for the overall survival of patients with hepatocellular carcinoma

Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinomaJournal of HepatologyVol. 77Issue 2PreviewThe highly proliferative nature of hepatocellular carcinoma (HCC) frequently results in a hypoxic intratumoural microenvironment, which creates a therapeutic challenge owing to a lack of mechanistic understanding of the phenomenon. We aimed to identify critical drivers of HCC development and progression in the hypoxic microenvironment. Full-Text PDF Open AccessReply to: ‘EFNA3 is a prognostic biomarker for the overall survival of patients with hepatocellular carcinoma’Journal of HepatologyVol. 77Issue 3PreviewEFNAs are functional predictors of overall survival in patients with hepatocellular carcinoma Full-Text PDF We read with great interest the article by Husain et al.,[1]Husain A. Chiu Y.T. Sze K.M. Ho D.W. Tsui Y.M. Suarez E.M.S. et al.Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma.J Hepatol. 2022; 77: 383-396Abstract Full Text Full Text PDF Scopus (5) Google Scholar showing that the expression of EFNA3 was upregulated in hepatocellular carcinoma (HCC) and related to poorer survival rates. Husain et al. found that the expression level of EFNA3 was regulated by HIF-1α in a hypoxic microenvironment. Hypoxia-induced Ephrin-A3/EphA2 forward signaling played a vital role in initiation and progression of HCC. The authors identified the clinical significance and molecular mechanisms of EFNA3 in HCC. However, the relationship between the HCC patients’ overall survival (OS) and EFNA3 was explored only based on The Cancer Genome Atlas (TCGA) database in their study. Without independent validation, evidence of the prognostic role of EFNA3 in HCC is not solid. Hence, the clinical observations regarding the beneficial effects of EFNA3 on OS in patients with HCC need to be confirmed in other independent cohorts.Previous studies showed that EFNA3 was a prognostic indicator of some types of tumors. For example, Zheng et al. demonstrated that upregulation of EFNA3 was correlated with worse survival rates in gastric cancer.[2]Zheng P. Liu X. Li H. Gao L. Yu Y. Wang N. et al.EFNA3 is a prognostic biomarker correlated with immune cell infiltration and immune checkpoints in gastric cancer.Front Genet. 2021; 12796592Google Scholar Dent et al. showed that high EFNA3 expression was significantly correlated with inferior survival in patients with lung adenocarcinoma.[3]Deng M. Tong R. Zhang Z. Wang T. Liang C. Zhou X. et al.EFNA3 as a predictor of clinical prognosis and immune checkpoint therapy efficacy in patients with lung adenocarcinoma.Cancer Cell Int. 2021; 21: 535Crossref PubMed Scopus (6) Google Scholar It is imperative to identify the relationships between EFNA3 and OS in patients with HCC based on multi-cohort data. Here, we collected two datasets that contain RNA sequencing (RNA-seq) profiles and follow-up survival information to validate the relationship between EFNA3 and OS in HCC. The first dataset liver cancer-RIKEN, JP (LIRI-JP) project, containing the RNA-seq and clinical follow-up data of 231 patients with HCC, was downloaded from the International Cancer Genome Consortium (ICGC) portal (https://dcc.icgc.org/).[4]Zhang J. Bajari R. Andric D. Gerthoffert F. Lepsa A. Nahal-Bose H. et al.The international cancer genome consortium data portal.Nat Biotechnol. 2019; 37: 367-369Crossref PubMed Scopus (140) Google Scholar The median age of these patients was 69, with 170 males and 61 females. Sixty-one patients had HBV infection. In total, 141 patients with HCC were classified as TNM stage 1 to 2. Another RNA-seq dataset that included 159 Chinese HCC(CHCC) patients was also retrieved from the literature.[5]Gao Q. Zhu H. Dong L. Shi W. Chen R. Song Z. et al.Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma.Cell. 2019; 179: 561-577 e522Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar In the CHCC cohort, all patients had HBV infection and the median age was 54, with 128 males and 31 females. The majority (105 out of 159, 66.0%) of patients with HCC were classified as TNM stage 1 to 2. Patients with HCC were stratified into 2 groups, a high-EFNA3 and a low-EFNA3 group, based on the median expression of EFNA3 in each cohort. The Kaplan–Meier plots showed that patients with HCC in the high-EFNA3 group had inferior survival in the LIRI-JP cohort (hazard ratio [HR] 3.25, 95% CI 1.77–5.96; p <0.001; Fig. 1A) and CHCC cohort (HR 2.31, 95% CI 1.37–3.91, p = 0.002; Fig. 1B).The article by Husain et al. provided novel insights into HCC clinical biomarker identification and molecular mechanisms.[1]Husain A. Chiu Y.T. Sze K.M. Ho D.W. Tsui Y.M. Suarez E.M.S. et al.Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma.J Hepatol. 2022; 77: 383-396Abstract Full Text Full Text PDF Scopus (5) Google Scholar We validated the prognostic value of EFNA3 in two HCC cohorts, which could further validate the findings from the TCGA database. In summary, we show that elevated EFNA3 expression represents an important OS predictor in patients with HCC. We are now carrying out immunochemical tests to further assess the clinical value of EFNA3.AbbreviationsCHCC, Chinese HCC patients; HCC, hepatocellular carcinoma; HR, hazard ratio ICGC, International Cancer Genome Consortium; TCGA, The Cancer Genome Atlas; OS, overall survival; RNA-seq, RNA sequencing; LIRI-JP, liver cancer-RIKEN, JP;Financial supportThis study was supported by the National Natural Science Foundation of China ( NSFC82160336 ).Authors’ contributionsPeng Lin and Hong Yang participated to data acquisition, statistical analysis, data interpretation, and writing of the manuscript. All authors approved the final version of the manuscript.Data availability statementData analyzed during the current study are available from the ICGC (https://icgc.org/, dataset ID: LIRI-JP,) and NODE (https://www.biosino.org/node, dataset ID: OEP000321). We read with great interest the article by Husain et al.,[1]Husain A. Chiu Y.T. Sze K.M. Ho D.W. Tsui Y.M. Suarez E.M.S. et al.Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma.J Hepatol. 2022; 77: 383-396Abstract Full Text Full Text PDF Scopus (5) Google Scholar showing that the expression of EFNA3 was upregulated in hepatocellular carcinoma (HCC) and related to poorer survival rates. Husain et al. found that the expression level of EFNA3 was regulated by HIF-1α in a hypoxic microenvironment. Hypoxia-induced Ephrin-A3/EphA2 forward signaling played a vital role in initiation and progression of HCC. The authors identified the clinical significance and molecular mechanisms of EFNA3 in HCC. However, the relationship between the HCC patients’ overall survival (OS) and EFNA3 was explored only based on The Cancer Genome Atlas (TCGA) database in their study. Without independent validation, evidence of the prognostic role of EFNA3 in HCC is not solid. Hence, the clinical observations regarding the beneficial effects of EFNA3 on OS in patients with HCC need to be confirmed in other independent cohorts. Previous studies showed that EFNA3 was a prognostic indicator of some types of tumors. For example, Zheng et al. demonstrated that upregulation of EFNA3 was correlated with worse survival rates in gastric cancer.[2]Zheng P. Liu X. Li H. Gao L. Yu Y. Wang N. et al.EFNA3 is a prognostic biomarker correlated with immune cell infiltration and immune checkpoints in gastric cancer.Front Genet. 2021; 12796592Google Scholar Dent et al. showed that high EFNA3 expression was significantly correlated with inferior survival in patients with lung adenocarcinoma.[3]Deng M. Tong R. Zhang Z. Wang T. Liang C. Zhou X. et al.EFNA3 as a predictor of clinical prognosis and immune checkpoint therapy efficacy in patients with lung adenocarcinoma.Cancer Cell Int. 2021; 21: 535Crossref PubMed Scopus (6) Google Scholar It is imperative to identify the relationships between EFNA3 and OS in patients with HCC based on multi-cohort data. Here, we collected two datasets that contain RNA sequencing (RNA-seq) profiles and follow-up survival information to validate the relationship between EFNA3 and OS in HCC. The first dataset liver cancer-RIKEN, JP (LIRI-JP) project, containing the RNA-seq and clinical follow-up data of 231 patients with HCC, was downloaded from the International Cancer Genome Consortium (ICGC) portal (https://dcc.icgc.org/).[4]Zhang J. Bajari R. Andric D. Gerthoffert F. Lepsa A. Nahal-Bose H. et al.The international cancer genome consortium data portal.Nat Biotechnol. 2019; 37: 367-369Crossref PubMed Scopus (140) Google Scholar The median age of these patients was 69, with 170 males and 61 females. Sixty-one patients had HBV infection. In total, 141 patients with HCC were classified as TNM stage 1 to 2. Another RNA-seq dataset that included 159 Chinese HCC(CHCC) patients was also retrieved from the literature.[5]Gao Q. Zhu H. Dong L. Shi W. Chen R. Song Z. et al.Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma.Cell. 2019; 179: 561-577 e522Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar In the CHCC cohort, all patients had HBV infection and the median age was 54, with 128 males and 31 females. The majority (105 out of 159, 66.0%) of patients with HCC were classified as TNM stage 1 to 2. Patients with HCC were stratified into 2 groups, a high-EFNA3 and a low-EFNA3 group, based on the median expression of EFNA3 in each cohort. The Kaplan–Meier plots showed that patients with HCC in the high-EFNA3 group had inferior survival in the LIRI-JP cohort (hazard ratio [HR] 3.25, 95% CI 1.77–5.96; p <0.001; Fig. 1A) and CHCC cohort (HR 2.31, 95% CI 1.37–3.91, p = 0.002; Fig. 1B). The article by Husain et al. provided novel insights into HCC clinical biomarker identification and molecular mechanisms.[1]Husain A. Chiu Y.T. Sze K.M. Ho D.W. Tsui Y.M. Suarez E.M.S. et al.Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma.J Hepatol. 2022; 77: 383-396Abstract Full Text Full Text PDF Scopus (5) Google Scholar We validated the prognostic value of EFNA3 in two HCC cohorts, which could further validate the findings from the TCGA database. In summary, we show that elevated EFNA3 expression represents an important OS predictor in patients with HCC. We are now carrying out immunochemical tests to further assess the clinical value of EFNA3. AbbreviationsCHCC, Chinese HCC patients; HCC, hepatocellular carcinoma; HR, hazard ratio ICGC, International Cancer Genome Consortium; TCGA, The Cancer Genome Atlas; OS, overall survival; RNA-seq, RNA sequencing; LIRI-JP, liver cancer-RIKEN, JP; CHCC, Chinese HCC patients; HCC, hepatocellular carcinoma; HR, hazard ratio ICGC, International Cancer Genome Consortium; TCGA, The Cancer Genome Atlas; OS, overall survival; RNA-seq, RNA sequencing; LIRI-JP, liver cancer-RIKEN, JP; Financial supportThis study was supported by the National Natural Science Foundation of China ( NSFC82160336 ). This study was supported by the National Natural Science Foundation of China ( NSFC82160336 ). Authors’ contributionsPeng Lin and Hong Yang participated to data acquisition, statistical analysis, data interpretation, and writing of the manuscript. All authors approved the final version of the manuscript. Peng Lin and Hong Yang participated to data acquisition, statistical analysis, data interpretation, and writing of the manuscript. All authors approved the final version of the manuscript. Data availability statementData analyzed during the current study are available from the ICGC (https://icgc.org/, dataset ID: LIRI-JP,) and NODE (https://www.biosino.org/node, dataset ID: OEP000321). Data analyzed during the current study are available from the ICGC (https://icgc.org/, dataset ID: LIRI-JP,) and NODE (https://www.biosino.org/node, dataset ID: OEP000321). The authors declare no conflicts of interest in this work. Please refer to the accompanying ICMJE disclosure forms for further details. We greatly appreciate the corresponding medical project for providing the public data (ICGC database and CHCC). Supplementary dataThe following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1 The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1