Bone morphogenetic protein 2 (BMP2) induces growth suppression and enhances chemosensitivity of human colon cancer cells

Abstract

BackgroundMolecular profiling of colorectal cancer (CRC) based on global gene expression has revealed multiple dysregulated signalling pathways associated with drug resistance and poor prognosis. However, the role of BMP2 signaling in CRC is not fully characterised.MethodsBioinformatics data analysis were conducted on the GSE21510 dataset. Leniviral technology was utilized to stably express BMP2 in the HCT116 CRC model. Gene expression profiling was conducted using Agilent microarray platform while data normalization and bioinformatics were conducted using GeneSpring software. Changes in gene expression were assessed using qRT-PCR. AlamarBlue assay was used to assess cell viability in vitro. In vivo experiments were conducted using SCID mice.ResultsOur data revealed frequent downregulation of BMP2 in primary CRC tissues. Additionally, interrogation of publically available gene expression datasets revealed significant downregulation of BMP2 in metastatic recurrent compared to non-metastatic cancer (p = 0.02). Global gene expression analysis in CRC cells over-expressing BMP2 revealed multiple dysregulated pathways mostly affecting cell cycle and DNA damage response. Concordantly, lentiviral-mediated re-expression of BMP2 inhibited HCT116 CRC growth, sphere formation, clonogenic potential, cell migration, and sensitized CRC cells to 5-fluorouracil (5-FU) in vitro. Additionally, BMP2 inhibited CRC tumor formation in SCID mice.ConclusionsOur data revealed an inhibitory role for BMP2 in CRC, suggesting that restoration of BMP2 expression could be a potential therapeutic strategy for CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0355-9) contains supplementary material, which is available to authorized users.

Upregulation of NETO2 gene in colorectal cancer

“…Inactivation of BMP signaling increases the tumorigenicity of normal colon stem cells. [ 59 ] [ 60 ] [ 61 ] VIM VIM is a Wnt-targeted gene that is expressed in normal mesenchymal cells, and that encodes the intermediate filament protein, vimentin. Previous studies have shown that vimentin mediates both cellular structure and integrity.…”

Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications

“…BMP7 has been linked with the metastatic capacity of colon cancer, while BMP2 has been linked with tumor suppression; therefore, BMP2 does not seem to be a part of tumor proliferation strategy. 46 , 47 , 48 It is interesting to note that SMAD4 is downregulated in colon cancer, while the BMP7 ability to promote the invasive behavior of colon cancer cells is independent of SMAD4 molecules. 49 , 50 , 51 BMP7 is not the only BMP to be linked with tumor proliferation in colon cancer.…”

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

“…In addition, colonic epithelia isolated from intestine specific and global CASR knockout mice demonstrated increased proliferation and increased WNT/CTNNB1 (β‐catenin) signaling . Also, stimulation of the CASR increased the expression of BMP2 (bone morphogenetic protein‐2), which induces growth suppression and enhances chemosensitivity of human colorectal cancer cells . Furthermore, CASR activation stimulated paracrine secretion of WNT5A from myofibroblasts and expression of ROR2 in epithelial cells .…”

“…15,39 Also, stimulation of the CASR increased the expression of BMP2 (bone morphogenetic protein-2), 40 which induces growth suppression and enhances chemosensitivity of human colorectal cancer cells. 41 Furthermore, CASR activation stimulated paracrine secretion of WNT5A from myofibroblasts and expression of ROR2 in epithelial cells. 42 CASR-mediated WNT5A/ROR2 interaction increased epithelial differentiation and reduced expression of the receptor for tumor necrosis factor 1.…”