Ubiquitin Associated Protein 2-Like (UBAP2L) Overexpression in Patients with Hepatocellular Carcinoma and its Clinical Significance

Abstract

BACKGROUND Recently, accumulating studies have shown that ubiquitin associated protein 2-like (UBAP2L) is overexpressed in many kinds of malignant tumors, which is closely associated to tumor growth and metastasis. However, the correlations of UBAP2L expression with clinicopathological factors and prognosis of hepatocellular carcinoma (HCC) patients still remain unclear. MATERIAL AND METHODS Bioinformatics database (GEO and TCGA) and our own experimental results (including immunohistochemical staining, western blotting and real-time PCR) were analyzed to validate the expression levels of UBAP2L in HCC. Furthermore, Kaplan-Meier survival analysis and Cox multivariate regression model were used to demonstrate the associations of UBAP2L expression with clinicopathological factors and prognosis of HCC patients. Additionally, the potential underlying mechanisms associated to angiogenesis were preliminarily explored. RESULTS Compared to the normal group, UBAP2L was significantly highly expressed in HCC cell lines and tissues. Kaplan-Meier survival analysis revealed that patients with high UBAP2L expression level had dramatically less survival time than those with low UBAP2L expression level (p=0.000). Moreover, multivariate Cox regression analysis showed that UBAP2L high expression was an independently unfavorable prognostic parameter for OS of HCC patients (p=0.000). Additionally, Pearson correlation analysis showed that the relationship between UBAP2L expression and VEGF or MVD was significantly positive, respectively (r=0.460, p=0.000 and r=0.387, p=0.000). CONCLUSIONS UBAP2L was overexpressed in HCC, and patients with high UBAP2L expression had unfavorable prognosis. UBAP2L could be a new potential therapeutic target for HCC in the future.

Figure 1

UBAP2L mRNA overexpression in HCC predicted by the Oncomine database. UBAP2L mRNA levels in (A) Roessler Liver (GEO: GSE 14520/GPL571), (B) Chen Liver (GEO: GSE 3500), (C) Roessler Liver2 (GEO: GSE 14520/GPL3921), and (D) Wurmbach Liver (GEO: GSE 6764) grouped by HCC and normal liver in Oncomine database.

Figure 2

UBAP2L mRNA overexpression and its correlation with overall survival time of HCC patients predicted by the TCGA database. TCGA database mining analysis of (A) UBAP2L mRNA levels grouped by HCC and normal liver and (B) correlation between UBAP2L mRNA and the OS of HCC patients, * p<0.05.

Figure 3

UBAP2L expression levels in HCC cell lines and tissues. (A) High expression of UBAP2L protein in four kinds of HCC cell lines (Hep3B, Huh-7, HepG2, and SMMC-7721) and hepatic normal cell line (L02). (B) Relative high UBAP2L mRNA level in HCC cell lines compared to the normal cell line, * p<0.05, ** p<0.01, *** p<0.001. (C) High expression of UBAP2L protein in four cases of fresh paired HCC and adjacent normal tissues, T – HCC, N – adjacent normal tissues.

Figure 4

Representative immunohistochemical images of UBAP2L in 90 cases of paired HCC and adjacent normal tissues: (A) High expression of UBAP2L in HCC tissue; (B) Low expression of UBAP2L in matched adjacent normal tissue; (C) Local magnification of (A); (D) Low expression of UBAP2L in HCC tissue. Bar=100 um.

Figure 5

Kaplan-Meier analysis of overall survival (OS) curves of HCC patients based on UBAP2L expression and other significantly meaningful indicators. (A) OS curve based on UBAP2L expression (high versus low); (B) OS curve based on tumor size (≤5c m versus >5 cm); (C) OS curve based on vascular invasion (Yes versus No); (D) OS curve based on TNM stage (I–II versus III–IV).

Figure 6

High co-expression of UBAP2L, VEGF, and CD34 in HCC tissues examined by immunohistochemistry. (A) UBAP2L high expression; (B) VEGF high expression; (C) CD34 high expression. Bar=100 um.

Figure 7

Relationship between UBAP2L expression and microvessel density (MVD) in HCC. (A) Differential MVD values grouped by UBAP2L high- or low-expression; (B) representative image of MVD in group of UBAP2L high expression; (C) representative image of MVD in group of UBAP2L low expression. MVD was calculated by the CD34 immunohistochemical staining. Bar=100 um.