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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.
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.
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.
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.
Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with 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.
Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with meta-analysis.
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,
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).
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.
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:
Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with meta-analysis.
Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway.
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