ITGB4 is a novel prognostic factor in colon cancer

Abstract

Integrin β4 (ITGB4) has been reported to be involved in carcinomas. Currently, ITGB4 has been characterized in colon cancer, however, its clinical significance is not very clear. In the present study, we utilized the large public datasets from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and collected clinical samples in our center to investigate the transcriptional expressions of ITGB4 in colon cancer, and then explored the associations of ITGB4 with clinicopathological features and overall survival. The statistical analyses suggested that ITGB4 mRNA expressions were up-regulated significantly in colon cancer. High ITGB4 expression was observed to be associated with elder onset age, proximal tumor location, and high microsatellite instability (MSH) status. Further, Kaplan-Meier curves and univariate analysis demonstrated high ITGB4 expression was significantly associated with unfavorable overall survival in colon cancer (HR=1.292, 95%CI=1.084-1.540, P=0.004). And significant association was also found after adjusting the confounding factors including age, gender, and stage (adjusted HR=1.254, 95%CI=1.050-1.497, P=0.012). The annotation of ITGB4 co-expressed genes suggested the pathways including cell growth, positive regulation of cell migration, and apoptotic signaling might be involved in the potential mechanisms of ITGB4 in colon cancer development. The molecular regulation mechanism of ITGB4 ectopic expression in colon cancer was also explored and the results indicated that ITGB4 might be up-regulated by the transcription factor FOSL1 (FOS like 1, AP-1 Transcription Factor Subunit) and its promoter hypomethylation. Our results revealed that ITGB4 might be a therapeutic target and prognosis marker for individual therapy of colon cancer.

Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

“…There have been a number of studies that have reported specific potential interactions of transcription factors with the ITGB4 promoter since its cloning [27] in a variety of cell types including RUNX1 [28], JUN [29] and KLF4 [30]. In CRC cells, MYC was the first transcription factor identified that promotes ITGB4 transcription [25] but recent studies have found others such as ZKSCAN3 [31] and FOSL1 [32] that need to be considered. Epigenetic regulation of ITGB4 expression has also been suggested after identification of microRNAs that may target the ITGB4 transcript such as miR-21 [33] and miR-335-5p [32] as well as hypomethylation of the ITGB4 promoter [32].…”

“…In CRC cells, MYC was the first transcription factor identified that promotes ITGB4 transcription [25] but recent studies have found others such as ZKSCAN3 [31] and FOSL1 [32] that need to be considered. Epigenetic regulation of ITGB4 expression has also been suggested after identification of microRNAs that may target the ITGB4 transcript such as miR-21 [33] and miR-335-5p [32] as well as hypomethylation of the ITGB4 promoter [32].…”

“…Based on the large public datasets that store this information as well as software that allows efficient data mining, it is becoming more and more affordable to analyze these data to compare their expression with pathological features and patient survival. In a recent study, Li et al [32] analyzed the relation of ITGB4 level expression in tumours with overall survival using four distinct NCBI GEO datasets as well as the TCGA dataset, selected on the basis of their size (more than 50 patients) and availability of overall survival information. Using the integrated data, high expression of ITGB4 in CRC was found to be significantly associated with an unfavorable overall survival rate indicating that it is a prognostic factor for colon cancer [32].…”

Revising the Role of Integrin Subunit β4 Expression in Colon Cancer Progression and Survival: A Retrospective Study

“…Several studies proposed that 4 is upregulated in carcinomas in comparison with normal mucosa or adenomas while others have found no relevant associations, or even diminished expression of 4 in invasive lesions. (19)(20)(21)(22)(23)(24)(25) Mishra and colleagues demonstrated that circulating tumor cells, as expected, had less adhesive properties, but also lower 4 expression as compared to the primary tumor. (26) It is expected that the cellular localization of this integrin also has profound impact on cell behavior as a basal, membranous localization is typical of normal colonic epithelium while diffuse 4 expression might correspond to an oncogenic pattern.…”

“…(2,8,10) Previous studies have failed to reach a consensus about a potential association between 4 expression and the aggressive phenotype invasive behavior of colorectal cancer cells. (19)(20)(21)(22)(23)(24)(25) Therefore, we sought to investigate the prognostic role of 4 expression in a large cohort of colon cancer patients.…”