BMP‑9 is a novel marker for colorectal tumorigenesis undergoing the normal mucosa‑adenoma‑adenocarcinoma sequence and is associated with colorectal cancer prognosis

Abstract

Depending on the type of cancer, bone morphogenetic protein-9 (BMP-9) can promote or inhibit tumorigenesis; however, the function of BMP-9 in colorectal cancer remains unclear. The aim of the present study was to evaluate the clinicopathological importance of BMP-9 expression in the tumorigenesis of normal colorectal epithelial tissue, and subsequent transformation into adenoma and carcinoma. In addition, the present study aimed to determine the prognostic value of BMP-9 on the survival of patients with colorectal cancer (CRC). A total of 65 patients with pathologically confirmed colorectal adenocarcinoma and a history of adenoma were enrolled. BMP-9 and Ki-67 expression was assessed retrospectively using paraffin-embedded samples of normal colorectal mucosa, colorectal adenoma and CRC obtained from each patient. The prognostic value of BMP-9 expression was analyzed in a group comprising 48 patients with CRC and a mean follow-up duration of 39.1 months. Bioinformatics analyses were performed in order to validate the results of the present study using published CRC datasets. The results from the present study suggested that the expression of BMP-9 gradually increased during the transition from normal mucosa to adenoma and subsequent adenocarcinoma (P<0.05); however, no significant association between the expression levels of BMP-9 and the clinicopathological parameters of patients was reported. Kaplan-Meier analysis revealed that patients with high expression levels of BMP-9 exhibited shorter overall survival rate than those with low levels of expression (54.7 vs. 41.3 months; log-rank test, P<0.05). Furthermore, regardless of tumor location and the presence of blood vessel tumor emboli, the univariate and multivariate analyses indicated that BMP-9 expression may be an independent prognostic factor for the overall survival rate of patients with CRC. The results of the present study suggested that BMP-9 may serve an oncogenic role and possess prognostic value in CRC.

Identification of liver‐derived bone morphogenetic protein (BMP)‐9 as a potential new candidate for treatment of colorectal cancer

“…We were able to define the ratio between expression of the BMP‐9‐target gene ID1 and the BMP‐inhibitor noggin as a new prognostic value in CRC. In contrast to the results of Fan et al, 10 our data strongly imply that by inducing ID1 expression BMP‐9 should be tumour‐suppressive in patients with CRC.…”

“…It seems that BMP‐9 can be both, a pro‐ as well as anti‐fibrogenic factor, 2,4‐7 and it can be pro‐ or anti‐proliferative to cancer cells 8,9 . Although the precise function of BMP‐9 in colorectal cancer remains unclear, a recent report by Fan et al implied that high local BMP‐9 expression might be associated with poor outcome in patients with CRC 10 . In this report, the authors investigated mRNA expression levels as well as protein presence of BMP‐9 in cancerous mucosa compared with normal mucosa, implying that in addition to the liver, the gut itself might be an important source for BMP‐9.…”

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

“…On the contrary, BMP signaling also acts as a pro-tumorigenic factor by promoting tumor invasion, epithelial-mesenchymal transition (EMT), and tumor proliferation ( Davis et al, 2016 ). Fan et al revealed that BMP-9 expression gradually increased during the transition from normal mucosa to adenoma and subsequent adenocarcinoma in the colon ( Fan et al, 2020 ). Our analysis showed that BMP-4 was highly expressed in CRC tissues compared to normal tissues, and that BMP-4 is involved in CRC progression as an autocrine factor ( Yokoyama et al, 2017 ).…”

Duality of bone morphogenetic proteins in cancer: A comprehensive analysis

“…Also, Cox proportional hazards model showed that higher BMP‐9 expression is an independent factor for the prediction of the prognosis in CRC patients. Thus, these findings indicated high BMP‐9 may be a prognostic marker in CRC patients and has a protumorigenic role in CRC tumorigenesis (Fan et al, 2020).…”

“…To determine the clinicopathological significance and prognostic value of BMP-9 in colon cancer, an immunohistochemical study was performed (Fan et al, 2020). Of note, this study revealed that the BMP-9 expression progressively increased within the cytoplasm or/ and membrane in tissues of high-grade tumors, from normal colorectal mucosa to adenoma and carcinoma (Fan et al, 2020).…”