Advertisement

Reply to: ‘EFNA3 is a prognostic biomarker for the overall survival of patients with hepatocellular carcinoma’

      Linked Article

      • Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma
        Journal of HepatologyVol. 77Issue 2
        • Preview
          The 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 Access
      • EFNA3 is a prognostic biomarker for the overall survival of patients with hepatocellular carcinoma
        Journal of HepatologyVol. 77Issue 3
        • Preview
          We read with great interest the article by Husain et al.,1 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.
        • Full-Text
        • PDF
      EFNAs are functional predictors of overall survival in patients with hepatocellular carcinoma
      To the Editor:
      We take delight in reading the report from Lin et al.
      • Lin P.
      • Yang H.
      EFNA3 is a prognostic biomarker for the overall survival of hepatocellular carcinoma patients.
      They refer to our study describing the functional and mechanistic roles of the Ephrin-A3/EphA2 axis in hypoxic hepatocellular carcinoma (HCC), where we utilized The Cancer Genome Atlas (TCGA) cohort of HCC cases to test the association of EFNA3 gene expression with overall survival (OS) rates of patients.
      • 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.
      Lin et al. have utilized 2 independent HCC cohorts i.e. liver cancer-REIKEN (LIRI-JP) and Chinese HCC (CHCC) datasets to validate our findings from TCGA cohort. These cohorts also show significant association of EFNA3 overexpression with poorer OS in patients with HCC. HBV infection is an etiological background known to have interactions with tumor hypoxia or its critical responders.
      • Lee S.W.
      • Lee Y.M.
      • Bae S.K.
      • Murakami S.
      • Yun Y.
      • Kim K.W.
      Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis.
      • Yoo Y.G.
      • Na T.Y.
      • Seo H.W.
      • Seong J.K.
      • Park C.K.
      • Shin Y.K.
      • et al.
      Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells.
      • Ding Z.N.
      • Dong Z.R.
      • Chen Z.Q.
      • Yang Y.F.
      • Yan L.J.
      • Li H.C.
      • et al.
      Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with meta-analysis.
      • Zheng S.S.
      • Chen X.H.
      • Yin X.
      • Zhang B.H.
      Prognostic significance of HIF-1α expression in hepatocellular carcinoma: a meta-analysis.
      The strong association of EFNA3 overexpression with survival rates in patients with HCC, despite the underlying etiological differences among the 3 cohorts of patients, suggests that EFNA3 expression has strong predictive value for OS in HCC patients.
      A closer look into the relation between Ephrin-As (EFNAs) and OS in patients with HCC can provide further insight into this predictive value. Other EFNAs, which are suggested to have significant functional overlap, i.e. EFNA4 and EFNA5, also demonstrate significant association with OS in patients with HCC in TCGA cohort, whereas this association is not seen in those that do not, i.e. EFNA1 and EFNA5. In our study, we found that tumor hypoxia and gain of chromosome 1q arm were the main drivers of EFNA3 expression and factors that could serve as confounding factors for the observed relationship.
      • Ding Z.N.
      • Dong Z.R.
      • Chen Z.Q.
      • Yang Y.F.
      • Yan L.J.
      • Li H.C.
      • et al.
      Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with meta-analysis.
      • Zheng S.S.
      • Chen X.H.
      • Yin X.
      • Zhang B.H.
      Prognostic significance of HIF-1α expression in hepatocellular carcinoma: a meta-analysis.
      • Chen L.
      • Yuan Y.F.
      • Li Y.
      • Chan T.H.
      • Zheng B.J.
      • Huang J.
      • et al.
      Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion.
      • Li J.T.
      • Liu W.
      • Kuang Z.H.
      • Chen H.K.
      • Li D.J.
      • Feng Q.S.
      • et al.
      Amplification of RIT1 in hepatocellular carcinoma and its clinical significance.
      • Zhang B.
      • Deng C.
      • Wang L.
      • Zhou F.
      • Zhang S.
      • Kang W.
      • et al.
      Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway.
      However, we observed that the expression of EFNA4 was a non-responder to hypoxia treatment and EFNA5 is located on 5q21.3, suggesting that the functional link between these genes may be the primal cause for their association with OS in patients with HCC. Since we had previously seen that the downstream mechanistic and functional consequence was not limited to EPNA3 and could be independent of the hypoxic microenvironment,
      • 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.
      we hypothesized that combining the expressions of EFNAs would hold stronger predictive power for OS in patients with HCC. In light of this, we stratified the TCGA cohort based on the expression of EFNA3, EFNA4 and EFNA5, or EFNA3 only to compare the OS rates among the groups. For stratification based on the expression of 3 genes, the upper quartile (Q3) for each gene was used as a threshold to classify as high or low. The median cut-off was used for stratification based on EFNA3 expression alone. Indeed, as seen from the Kaplan-Meier plots, the predictive power of the 3 genes combined for OS in HCC (hazard ratio [HR] 2.204, 95% CI 1.562 to 3.110, p = 0.0004) is more effective compared to EFNA3 alone (HR 1.42, 95% CI 1.008 to 2.000, p = 0.032) (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Kaplan-Meier plot showing the overall survival of patients with HCC stratified by expression of EFNA3, EFNA4 and EFNA5, or EFNA3 within TCGA cohort.
      Log-rank (Mantel-Cox) test (∗p <0.05, ∗∗∗p <0.001).
      The report from Lin et al. and our prior study provided evidence for the functional link between OS and expression of EFNA3 in patients with HCC.
      • Lin P.
      • Yang H.
      EFNA3 is a prognostic biomarker for the overall survival of hepatocellular carcinoma patients.
      ,
      • 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.
      Here we further investigated the link between the expression of other EFNAs with OS in patients with HCC and found that considering the expression of the combination of EFNA3, EFNA4 and EFNA5 could provide better predictive value. This association warrants confirmation in other independent HCC cohorts at the RNA and protein level.

      Financial support

      The study was supported by Theme-based Research Scheme (T12-704/16- R), Hong Kong Health and Medical Research Fund (06172886), Innovation and Technology Commission grant for State Key Laboratory of Liver Research, University Development Fund of The University of Hong Kong, and Loke Yew Endowed Professorship award. I.O.L. Ng is Loke Yew Professor in Pathology.

      Authors’ contributions

      Abdullah Husain, Yung-Tuen Chiu and Irene Oi-Lin Ng participated in data acquisition, statistical analysis, data interpretation, and writing of the manuscript. All authors approved the final version of the manuscript.

      Data availability statement

      TCGA dataset for HCC patients were obtained and are available from UCSC Xena (https://xenabrowser.net).

      Conflict of interest

      The authors declare no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgement

      We highly appreciate the availability of The Cancer Genome Atlas (TCGA) dataset.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Lin P.
        • Yang H.
        EFNA3 is a prognostic biomarker for the overall survival of hepatocellular carcinoma patients.
        J Hepatol. 2022; 77: 879-880
        • 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: 383-396
        • Lee S.W.
        • Lee Y.M.
        • Bae S.K.
        • Murakami S.
        • Yun Y.
        • Kim K.W.
        Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis.
        Biochem Biophys Res Commun. 2000; 268: 456-461
        • Yoo Y.G.
        • Na T.Y.
        • Seo H.W.
        • Seong J.K.
        • Park C.K.
        • Shin Y.K.
        • et al.
        Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells.
        Oncogene. 2008; 27: 3405-3413
        • Ding Z.N.
        • Dong Z.R.
        • Chen Z.Q.
        • Yang Y.F.
        • Yan L.J.
        • Li H.C.
        • et al.
        Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with meta-analysis.
        J Gastroenterol Hepatol. 2021; 36: 1487-1496
        • Zheng S.S.
        • Chen X.H.
        • Yin X.
        • Zhang B.H.
        Prognostic significance of HIF-1α expression in hepatocellular carcinoma: a meta-analysis.
        PLoS One. 2013; 8e65753
        • Chen L.
        • Yuan Y.F.
        • Li Y.
        • Chan T.H.
        • Zheng B.J.
        • Huang J.
        • et al.
        Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion.
        Gut. 2011; 60: 534-543
        • Li J.T.
        • Liu W.
        • Kuang Z.H.
        • Chen H.K.
        • Li D.J.
        • Feng Q.S.
        • et al.
        Amplification of RIT1 in hepatocellular carcinoma and its clinical significance.
        Ai Zheng. 2003; 22: 695-699
        • Zhang B.
        • Deng C.
        • Wang L.
        • Zhou F.
        • Zhang S.
        • Kang W.
        • et al.
        Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway.
        Mol Carcinog. 2018; 57: 201-215