Abstract
Colorectal cancer (CRC) is a complex and heterogeneous disease with four consensus molecular subtypes (CMS1-4). LTBP2 is a member of the fibrillin/LTBP super family and plays a critical role in tumorigenesis by activating TGF-β in the CMS4 CRC subtype. So far, the expression and prognostic significance of LTBP2 in CRC remains obscure. In this study, we aimed to analyze the mRNA and protein expression levels of LTBP2 in CRC tissues and then estimate their values as a potential prognostic biomarker. We detected the mRNA expression of LTBP2 in 28 cases of fresh CRC tissues and 4 CRC cell lines and the protein expression of LTBP2 in 483 samples of CRC tissues, matched tumor-adjacent tissues, and benign colorectal diseases. LTBP2 protein expression was then correlated to patients' clinical features and overall survival. Both LTBP2 mRNA and protein expression levels in CRC tissues were remarkably superior to those in adjacent normal colorectal tissues (P = 0.0071 and P < 0.001, respectively), according to TCGA dataset of CRC. High LTBP2 protein expression was correlated with TNM stage (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and M stage (P < 0.001). High LTBP2 protein expression was related to poor overall survival in CRC patients and was an independent prognostic factor for CRC. LTBP2 mRNA expression was especially higher in the CMS4 subtype (P < 0.001), which was confirmed in CRC cell lines. Our data suggested that LTBP2 may act as an oncogene in the development of colorectal cancer and have important significance in predicting CRC prognosis. LTBP2 could be a novel biomarker and potential therapeutic target for mesenchymal colorectal cancer and can improve the outcome of high-risk CRC.
Highlights
Colorectal cancer (CRC) demonstrates extremely heterogeneous and complex gastrointestinal malignancy, with increasing incidence and mortality according to the newest statistical survey [1]
LTBP2 mRNA expression was significantly higher in CRC tissues than in matched adjacent tissues (P = 0 0071, Figure 1(a)), in accord with The Cancer Genome Atlas (TCGA) database (P < 0 0001, Figure 1(b))
High LTBP2 protein expression was detected in 28.4% of CRC tissues, which was significantly higher compared with the expression detected in 4.3% of chronic colitis tissues, in 6.8% of low-grade intraepithelial neoplasia tissues, in 22.7% of high-grade intraepithelial neoplasia tissues, and in 6.8% of the surgical margin (Pearson χ2 = 39 896, P < 0 001) (Table 1)
Summary
Colorectal cancer (CRC) demonstrates extremely heterogeneous and complex gastrointestinal malignancy, with increasing incidence and mortality according to the newest statistical survey [1]. Despite the remarkable advances in the management of CRC in recent years, the 5-year overall survival (OS) rate is still poor [2, 3]. General thinking suggests that genetic alterations, including somatic gene mutation, deletion, or amplification, copy number variation, and epigenetic modifications, facilitate initiation and progression of CRC. CMS4 is closely related to recurrence and metastasis, and the underlying mechanisms include transforming growth factor β (TGF-β) activation, stromal invasion, and angiogenesis. It is usually at a relatively later tumor stage when it is diagnosed, and it contributes to worse relapse-free and overall survival rate [7].
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