BMP3 suppresses colon tumorigenesis via ActRIIB/SMAD2-dependent and TAK1/JNK signaling pathways
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Published on: October 27, 2020
Jialing Wen1, Xianglin Liu2, Yan Qi2
1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Background:
BMP3 gene is often found hypermethylated and hence inactivated in several types of cancers including colorectal cancer (CRC), indicating that it has a suppressor role in carcinogenesis. Though BMP3 is a reliable biomarker for screening CRC, the molecular mechanism of BMP3 in carcinogenesis remains largely unknown.
Methods:
The expression level of BMP3 was examined by immunohistochemistry staining and western blot. Methylation-specific PCR (MSP) and real-time quantitative MSP were used to test the hypermethylation status of BMP3 gene. Analyses of BMP3 function in colon cancer cell proliferation, migration, invasion, and apoptosis were performed using HCT116 and KM12 cells. BMP3 was further knocked down or overexpressed in CRC cells, and the effects on cell growth of xenograft tumors in nude mice were assessed. Co-immunoprecipitation and immunofluorescence staining were used to analyze the association between BMP3 and BMPR2 or BMP3 and ActRIIB. Microarray analysis was performed to identify most differentially expressed genes and pathways regulated by BMP3. The BMP3-regulated SMAD2-dependent signaling pathway and TAK1/JNK signal axes were further investigated by quantitative PCR and western blot.
Results:
BMP3 gene was hypermethylated and its expression was downregulated in both CRC tissues and cell lines. Expressing exogenous BMP3 in HCT116 inhibited cell growth, migration, and invasion and increased rate of apoptosis both in vitro and in vivo. However, shRNA-mediated attenuation of endogenous BMP3 in KM12 reversed such inhibitory and apoptotic effects. Furthermore, BMP3 could bind to ActRIIB, an activin type II receptor at the cellular membrane, thereby activating SMAD2-dependent pathway and TAK1/JNK signal axes to regulate downstream targets including caspase-7, p21, and SMAD4 that play crucial roles in cell cycle control and apoptosis.
Conclusions:
Our study reveals a previously unknown mechanism of BMP3 tumor suppression in CRC and provides a rationale for future investigation of BMP3 as a potential target for the development of novel therapeutic agents to fight CRC.
Insights
Bone morphogenetic protein 3 (BMP3) acts as a tumor suppressor in colorectal cancer (CRC) by inhibiting cell growth and promoting apoptosis. Its inactivation through hypermethylation reveals a new therapeutic target for CRC treatment.
Area of Science:
- Molecular biology
- Oncology
- Cancer research
Background:
- Bone morphogenetic protein 3 (BMP3) is frequently hypermethylated and inactivated in colorectal cancer (CRC), suggesting a tumor suppressor role.
- While BMP3 is a known biomarker for CRC screening, its precise molecular mechanisms in carcinogenesis are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism of BMP3's tumor suppressive function in colorectal cancer.
- To investigate the signaling pathways regulated by BMP3 in CRC cells.
- To explore the potential of BMP3 as a therapeutic target for CRC.
Main Methods:
- Examined BMP3 expression using immunohistochemistry and western blot.
- Assessed BMP3 gene hypermethylation via methylation-specific PCR (MSP).
- Analyzed BMP3 function in CRC cell lines (HCT116, KM12) and in vivo xenograft models, including knockdown and overexpression studies.
- Investigated BMP3 interactions with ActRIIB and downstream signaling pathways (SMAD2, TAK1/JNK) using co-immunoprecipitation, immunofluorescence, and western blot.
Main Results:
- BMP3 was found to be hypermethylated and downregulated in CRC tissues and cell lines.
- Exogenous BMP3 expression inhibited CRC cell proliferation, migration, and invasion while enhancing apoptosis in vitro and in vivo.
- BMP3 binds to ActRIIB, activating the SMAD2 and TAK1/JNK pathways, which regulate key apoptosis and cell cycle control proteins (caspase-7, p21, SMAD4).
Conclusions:
- This study uncovers a novel mechanism of BMP3-mediated tumor suppression in colorectal cancer.
- BMP3's interaction with ActRIIB and subsequent activation of SMAD2 and TAK1/JNK pathways are critical for its anti-cancer effects.
- BMP3 presents a promising target for developing new therapeutic strategies against CRC.
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