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

We read with great interest the article by Husain et al., 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. Dent et al. showed that high EFNA3 expression was significantly correlated with inferior survival in patients with lung adenocarcinoma. 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/). 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. 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. 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.