Clinical Significance of BMP7 in Human Colorectal Cancer

Department of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumibaru, Beppu, 874-0838, Japan.
Annals of Surgical Oncology (Impact Factor: 3.93). 05/2008; 15(5):1530-7. DOI: 10.1245/s10434-007-9746-4
Source: PubMed


Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor (TGF)-beta superfamily. Recent studies demonstrated that the expression patterns of BMPs are altered in several tumors. The purpose of the current study was to examine the expression of BMP7 in malignant and normal colorectal tissues, and to analyze whether BMP7 expression levels correlate with clinicopathological variables and prognosis in colorectal cancer.
Paired colorectal tissue samples from cancer and corresponding nonmalignant tissues were obtained from 65 patients who underwent surgical resection for colorectal cancer. The expression status of BMP7 mRNA was investigated by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and protein expression was analyzed by an immunohistochemical study.
Quantitative real-time RT-PCR showed that BMP7 mRNA expression in cancerous tissue was significantly higher than that in normal tissue (p < 0.0001). An immunohistochemical study revealed that BMP7 was predominantly expressed in cancer cells. Elevated BMP7 expression was significantly correlated with depth of tumor invasion, liver metastasis, liver recurrence, advanced Dukes' classification, and cancer-related death (p < 0.05, 0.001, 0.01, 0.05 and 0.01, respectively). Furthermore, patients with the highest levels of BMP7 expression showed the poorest prognosis (p < 0.01). A multivariate analysis showed that BMP7 expression status was an independent prognostic factor of overall survival (relative risk, 2.29; 95% confidence interval, 1.08-5.30; p < 0.05).
Expression of BMP7 in colorectal tumors correlates with parameters of pathological aggressiveness such as liver metastasis and poor prognosis. Thus, BMP7 could be a useful clinical marker for colorectal cancer patients.

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    • "This remained significant even with the parallel administration of 50 ng/ml of BMP7 (Figure 7B; upper panel). However, the addition of BMP7 alone did not significantly affect the epithelial phenotype or ability of HT29 cells to form their typical cohorts/colonies (Figure 7A), an observation that further strengthens the notion that BMP7 promotes the integrity and maintenance of the epithelial phenotype ( Motoyama et al., 2008 ). As subjective to a certain extent, these results were further confirmed through computerassisted determination of cell circularity index (Figure 7B; lower panel), as previously described ( Shen et al., 2014 ). "
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    ABSTRACT: Abstract Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e. cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight-junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin - upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.
    Biological Chemistry 08/2014; 396(2). DOI:10.1515/hsz-2014-0221 · 3.27 Impact Factor
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    • "For example, several BMPs were found to be growth suppressive and may have their promoters methylated in colon cancer, compatible with a tumor-suppressor role for BMPs in CRC (16–18). However, the expression of BMP4 and BMP7 was found to increase with progression through the adenoma-carcinoma sequence and to correlate with a worse prognosis (19,20). A more recent report showed that BMP signaling promotes the growth of primary human colon cancer in vivo (21). "
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    ABSTRACT: Colorectal cancer (CRC) is one of the most deadly cancers worldwide. Significant progress has been made in understanding the molecular pathogenesis of CRC, which has led to successful early diagnosis, surgical intervention and combination chemotherapy. However, limited therapeutic options are available for metastatic and/or drug-resistant CRC. While the aberrantly activated Wnt/β-catenin pathway plays a critical initiating role in CRC development, disruption of the bone morphogenetic protein (BMP) pathway causes juvenile polyposis syndrome, suggesting that BMP signaling may play a role in CRC development. However, conflicting results have been reported concerning the possible roles of BMP signaling in sporadic colon cancer. Here, we investigated the effect of BMP2 on the proliferation, migration, invasiveness and tumor growth capability of human CRC cells. Using an adenovirus vector that overexpresses BMP2 and the piggyBac transposon-mediated stable BMP2 overexpression CRC line, we found that exogenous BMP2 effectively inhibited HCT116 cell proliferation and colony formation. BMP2 was shown to suppress colon cancer cell migration and invasiveness. Under a low serum culture condition, forced expression of BMP2 induced a significantly increased level of apoptosis in HCT116 cells. Using a xenograft tumor model, we found that forced expression of BMP2 in HCT116 cells suppressed tumor growth, accompanied by decreased cell proliferation activity. Taken together, our results strongly suggest that BMP2 plays an important inhibitory role in governing the proliferation and aggressive features of human CRC cells.
    Oncology Reports 07/2014; 32(3). DOI:10.3892/or.2014.3308 · 2.30 Impact Factor
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    • "Bone Morphogenetic protein 7 (BMP7) (2.41-fold increase), also known as osteogenic protein 1 (OP-1), encodes a multifunctional growth factor belonging to the TGF-β superfamily. Elevated BMP7 levels are reported to be correlated with the depth of colorectal tumor invasion, liver metastasis and cancer-related death [60], as well as the levels of estrogen and progesterone receptor, both of which are important markers for breast cancer prognosis and therapy [61]. Similarly, GDF15 (4.49-fold increase), which encodes another member of the TGF-β superfamily, was reported to exert proapoptotic and anti-tumorigenic functions on colorectal, prostate, and breast cancer cells in vitro and on colon and blioblastoma tumors in vivo[62]. "
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    ABSTRACT: Background The circadian clock and cell cycle are two global regulatory systems that have pervasive behavioral and physiological effects on eukaryotic cells, and both play a role in cancer development. Recent studies have indicated that the circadian and cell cycle regulator, TIMELESS, may serve as a molecular bridge between these two regulatory systems. Methods To assess the role of TIMELESS in tumorigenesis, we analyzed TIMELESS expression data from publically accessible online databases. A loss-of-function analysis was then performed using TIMELESS-targeting siRNA oligos followed by a whole-genome expression microarray and network analysis. We further tested the effect of TIMELESS down-regulation on cell proliferation rates of a breast and cervical cancer cell line, as suggested by the results of our network analysis. Results TIMELESS was found to be frequently overexpressed in different tumor types compared to normal controls. Elevated expression of TIMELESS was significantly associated with more advanced tumor stage and poorer breast cancer prognosis. We identified a cancer-relevant network of transcripts with altered expression following TIMELESS knockdown which contained many genes with known functions in cancer development and progression. Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate. Conclusions Our results suggest a potential role for TIMELESS in tumorigenesis, which warrants further investigation of TIMELESS expression as a potential biomarker of cancer susceptibility and prognostic outcome.
    BMC Cancer 10/2013; 13(1):498. DOI:10.1186/1471-2407-13-498 · 3.36 Impact Factor
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