Suppression of tumorigenesis and activation of Wnt signaling by bone morphogenetic protein 4 in human cancer cells

Abstract

Aberrations in BMP signaling have recently been implicated as a cause of human cancer. Here we demonstrate and define the tumor suppressive properties of BMP4. Consistent with its potential role in a tumor suppressor pathway, BMP4 treatment eliminated the tumorigenic potential of an undifferentiated human cancer cell line. This loss of tumorigenicity was accompanied by an increase in apoptosis, alterations in cell cycle profile, and an increase in cell size. Interestingly, human colon cancer cells were resistant to the growth-suppressive properties of BMP4. To identify putative downstream mediators of BMP4-mediated tumor suppression, Affymetrix Genechips were employed to identify BMP4-regulated genes. The human BMP4 transcriptome was characterized by the modulation of many genes well known to play important roles in differentiation and development, including the induction of numerous genes involved in Wnt signaling. Modulation of Wnt gene expression by BMP4 had several functional consequences--BMP4 treatment led to activation of TCF reporters; complete activation of at least one BMP4-responsive gene required TCF sites; and treatment with a Wnt ligand was sufficient to mimic several of the phenotypic effects of BMP4 treatment. These data demonstrate the tumor suppressive properties of BMP4 signaling, show that colon cancer cells are resistant to BMP4-induced differentiation and growth suppression, further define the BMP4 transcriptome, and raise the intriguing possibility that interactions between the Wnt and BMP signaling pathways may play an important role in differentiation and tumor suppression.

SMAD6 Contributes to Patient Survival in Non–Small Cell Lung Cancer and Its Knockdown Reestablishes TGF-β Homeostasis in Lung Cancer Cells

“…S1 B ). The mRNA level of Smad7 was unchanged in the tested cells (Supplementary Table S5) and no genes associated with the induction of BMP signaling were observed (18). …”

“…Our Western experiments showed that SMAD7 is expressed uniformly and at much higher levels than SMAD6 in both normal and cancer cells derived from the lung but is induced to a much less extent on TGF-β and BMP stimulation (data not shown). Similarly, down-regulation of SMAD6 by shRNA did not affect the expression of Smad7 or affected genes commonly involved in BMP induction (18). …”

Single Nucleotide Polymorphisms in the Wnt and BMP Pathways and Colorectal Cancer Risk in a Spanish Cohort

“…Both Wnt and BMP pathways were initially selected after the findings of Nishanian et al [34], who demonstrated the interaction between these two pathways. Both pathways were thoroughly investigated through the Cancer Genome Anatomy Project site [35], but we failed to find any information regarding the BMP pathway in either this or other web browsers.…”

“…Both pathways were thoroughly investigated through the Cancer Genome Anatomy Project site [35], but we failed to find any information regarding the BMP pathway in either this or other web browsers. For that reason, Wnt genes were selected by browsing the pathway through Biocarta [36], whereas BMP genes had to be strictly selected from previous literature [17], [34]. Forty-one genes were finally selected to be included in the analysis.…”

Effects of interactions between common genetic variants and smoking on colorectal cancer

“…A similar positive interaction was also observed between rs17563 on BMP4 and smoking for CRC risk in a previous study [ 47 ] in spite of little linkage disequilibrium between rs1957636 and rs17563 (r 2 = 0.12 in HapMap3 JPT + CHB + CHD individuals). Biologically, BMP signaling has been suggested to cause human cancer through its tumor suppressor properties, but colon cancer cells were resistant to the growth suppression and differentiation induced by BMP4 [ 48 ]. Experiments conducted using a rat model showed that BMP4 was up-regulated by chronic cigarette smoking [ 49 ].…”