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. 2018 Feb 28;9(6):1088-1095.
doi: 10.7150/jca.23639. eCollection 2018.

Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer

Chen-Hui Luo  1   2 , Min Zhao  1 , Yu-Xi Tang  3 , Shohreh Shahabi  4 , Kai-Ning Fang  3 , Yan Chen  3 , Yan Tang  3 , Xiao-Yan Chen  5 , Jing Wang  3 , Hong-Hao Zhou  1
Affiliations

Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer

Chen-Hui Luo et al. J Cancer. .

Abstract

Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations.

Keywords: HE4; eIF3a; epithelial ovarian cancer (EOC); mRNA; overall survival.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
(A) Levels of HE4 mRNA, eIF3a mRNA, and serum CA125 among tumors. HE4 mRNA and serum CA125 levels were significantly increased in malignant tumors. (B) ROC curves for discrimination of malignant tumors from benign and borderline tumors using HE4 mRNA levels. The area under curve (AUC) for Benign vs. Malignant and Borderline vs. Malignant were 0.842 (95%CI, 0.775-0.909) and 0.710 (95%CI, 0.599-0.821), respectively. Both P<0.01. (C) Correlations of HE4 mRNA with serum CA125 and eIF3a mRNA. Spearman's and Pearson's correlation test were used, respectively.
Figure 2
Figure 2
Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) of women with EOC. (A) OS curves indicated the prolonged OS of patients with HE4 mRNA level greater than 1, 10, 50, and 100 compared to less than 1. All P<0.05. (B) PFS curve indicated patients with eIF3a mRNA level in the first quartile (<25%) recurred earlier than those in the upper fourth quartile (>75%). P=0.075. PFS curve (C) and OS curve (D) for HE4 protein levels detected by IHC indicated worse survival of patients with high expression of HE4 protein than those with low expression of HE4 protein. P=0.093 and 0.022, respectively.
Figure 3
Figure 3
The representative images of HE4 staining by IHC in ovarian tissues at 100× and 200× magnification. (A) High expression, (B) Low expression.
See this image and copyright information in PMC

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