High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma

Xiaolong Du,Chuanzheng Yin,Zifang Song,Xichuan Zheng,Chen Zhang,Min Li,Dawei Xie,Xueke Yan,Qichang Zheng,Wenjie Wang

doi:10.3389/fonc.2021.633899

Abstract

Molecular mechanisms underlying the tumorigenesis of a highly malignant cancer, cholangiocarcinoma (CCA), are still obscure. In our study, the CCA expression profile data were acquired from The Cancer Genome Atlas (TCGA) database, and differentially expressed genes (DEGs) in the TCGA-Cholangiocarcinoma (TCGA-CHOL) data set were utilized to construct a co-expression network via weighted gene co-expression network analysis (WGCNA). The blue gene module associated with the histopathologic grade of CCA was screened. Then, five candidate hub genes were screened by combining the co-expression network with protein–protein interaction (PPI) network. After progression and survival analyses, bloom syndrome helicase (BLM) was ultimately identified as a real hub gene. Moreover, the receiver operating characteristic (ROC) curve analysis suggested that BLM had a favorable diagnostic and predictive recurrence value for CCA. The gene set enrichment analysis (GSEA) results for a single hub gene revealed the importance of cell cycle-related pathways in the CCA progression and prognosis. Furthermore, we detected the BLM expression in vitro, and the results demonstrated that the expression level of BLM was much higher in the CCA tissues and cells relative to adjacent non-tumor samples and normal bile duct epithelial cells. Additionally, after further silencing the BLM expression by small interfering RNA (siRNA), the proliferation and migration ability of CCA cells were all inhibited, and the cell cycle was arrested. Altogether, a real hub gene (BLM) and cell cycle-related pathways were identified in the present study, and the gene BLM may be involved in the CCA progression and could act as a reliable biomarker for potential diagnosis and prognostic evaluation.

Highlights

Cholangiocarcinoma (CCA) is one of the most frequent primary biliary duct malignancies and accounts for 3% of all gastrointestinal neoplasias [1, 2]
The module that was most significantly correlated with a tumor grade indicated a great value in predicting the CCA progression, and the ME of the blue module indicated its high correlation with the CCA progression (Figure 2D)
We found that the module significance (MS) of the blue module was the highest among all the modules that were positively correlated with disease progression (Figure 2E)

Summary

Introduction

Cholangiocarcinoma (CCA) is one of the most frequent primary biliary duct malignancies and accounts for 3% of all gastrointestinal neoplasias [1, 2]. Since CCA possesses the characteristics of high malignancy, insidious onset, and rapid progression, the prognosis of patients with CCA is often poor [3, 4]. In the USA alone, CCA accounts for approximately 5,000 deaths per year [6]. Since its early symptoms are not obvious and CCA lacks a highly efficient disease screening biomarker, many patients have frequently lost the chance of radical surgery upon the first diagnosis [7]. There is an urgent need to explore the molecular pathogenesis of CCA and reveal the biomarkers closely related to the diagnosis, occurrence, progression, and prognosis of CCA

Methods

Results

Discussion

Conclusion