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Identification of LIFR, PIK3R1, and MMP12 as Novel Prognostic Signatures in Gallbladder Cancer Using Network-Based Module Analysis.

ABSTRACT: Background: Gallbladder cancer (GBC) is a rare and aggressive malignancy of the biliary tract with a dismal survival rate. Effective biomarkers and therapeutic targets are urgently needed. Methods: We analyzed gene expression profiles of GBC to identify differentially expressed genes (DEGs) and then used these DEGs to identify functional module biomarkers based on protein functional interaction (FI) networks. We further evaluated the module-gene protein expression and clinical significance with immunohistochemistry staining (IHC) in a tissue microarray (TMA) from 80 GBC samples. Results: Five functional modules were identified. Module 0 included classical cancer signaling pathways, such as Ras and PI3K-Akt; and modules 1-4 included genes associated with muscle cells, fibrinogen, extracellular matrix, and integrins, respectively. We validated the expression of LIFR, PIK3R1, and MMP12, which were hubs or functional nodes in modules. Compared with paired peritumoural tissues, we found that the expression of LIFR (P = 0.002) and PIK3R1 (P = 0.046) proteins were significantly downregulated, and MMP12 (P = 0.006) was significantly upregulated. Further prognostic analysis showed that patients with low expression of LIFR had shorter overall survival than those with high expression (log-rank test P = 0.028), the same trend as for PIK3R1 (P = 0.053) and MMP12 (P = 0.006). Multivariate analysis indicated that expression of MMP12 protein (hazard ratio [HR] = 0.429; 95% confidence interval [CI] 0.198, 0.930; P = 0.032) was one of the significant independent prognostic factors for overall survival. Conclusions: We found a highly reliable FI network, which revealed LIFR, PIK3R1, and MMP12 as novel prognostic biomarker candidates for GBC. These findings could accelerate biomarker discovery and therapeutic development in this cancer.

SUBMITTER: Zhao X

PROVIDER: S-EPMC6504688 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of LIFR, PIK3R1, and MMP12 as Novel Prognostic Signatures in Gallbladder Cancer Using Network-Based Module Analysis.

Zhao Xinyi X Xu Mengxiang M Cai Zhen Z Yuan Wenji W Cui Wenyan W Li Ming D MD

Frontiers in oncology 20190501

Background: Gallbladder cancer (GBC) is a rare and aggressive malignancy of the biliary tract with a dismal survival rate. Effective biomarkers and therapeutic targets are urgently needed. Methods: We analyzed gene expression profiles of GBC to identify differentially expressed genes (DEGs) and then used these DEGs to identify functional module biomarkers based on protein functional interaction (FI) networks. We further evaluated the module-gene protein expression and clinical sign ...[more]

PMID: 31119098

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Project description:Gallbladder cancer is the most common biliary tract malignant tumor, with unfavorable patient outcomes. The present study aimed to identify potential diagnostic or prognostic biomarkers for gallbladder cancer. To do so, differentially expressed genes in the gallbladder walls and tumor tissues of patients with gallbladder cancer were analyzed via microarray. Furthermore, a protein-protein interaction network was constructed and genes with a degree score >10 were selected as hub genes. As ubiquitin conjugating enzyme E2T (UBE2T) was considered to be a hub gene, its expression was assessed via reverse transcription-quantitative (RT-q)PCR and immunohistochemistry (IHC). In addition, the association between UBE2T expression and the clinicopathological characteristics of patients with gallbladder cancer was analyzed using the ?2 test. Furthermore, all patients were divided into high- and low groups based on UBE2T expression level and overall survival analysis was performed. Univariate and multivariate Cox regression analyses were performed to determine whether UBE2T may serve as an independent risk factor for gallbladder cancer. The results demonstrated that UBE2T expression was upregulated in the gallbladder walls and tumor tissues of patients with gallbladder cancer. Furthermore, UBE2T expression level was confirmed to be upregulated following RT-qPCR, and results from IHC demonstrated that UBE2T was predominantly expressed in the cytoplasm of gallbladder cancer cells. In addition, high UBE2T expression level was associated with clinical stage, T classification, N classification and M classification. The results from Univariate and multivariate analyses indicated that UBE2T expression level may be considered as an independent risk factor for gallbladder cancer. Taken together, the findings from this study suggested that high UBE2T expression level may contribute to the poor prognosis of patients with gallbladder cancer, and that UBE2T may act as an independent prognostic biomarker for these patients.

Dataset Information

Identification of LIFR, PIK3R1, and MMP12 as Novel Prognostic Signatures in Gallbladder Cancer Using Network-Based Module Analysis.

Publications

Identification of <i>LIFR, PIK3R1</i>, and <i>MMP12</i> as Novel Prognostic Signatures in Gallbladder Cancer Using Network-Based Module Analysis.

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