Hu Zhuowei’s Group Has Made Breakthroughs in the Study on Molecular Mechanism of Colon Cancer Incidence

2018-10-30

The incidence of colorectal cancer in the world remains high. However, in recent years, it is also on the rise in China. Due to its complicated pathogenesis and unclear pathogenetic process, the main clinical treatment for patients after colon cancer surgery is still the chemotherapy with cytotoxic agents such as 5-fluorouraci+oxaliplatin (FOLFOX) or capecitabine+oxaliplatin (XELOX). Such drugs have strong toxic side effects and poor targeting, and are easy to produce drug resistance. Usually, these weaknesses cannot contribute to good efficacy, but increase the pain of patients. These phenomena urge researchers to further explore the pathogenesis of colon cancer and find potential therapeutic targets and drugs. The research results concluded by the group of Hu Zhuowei, Principle Investigator of the State Key Laboratory of Bioactive Substances and Functions of Natural Medicines (Institute of Materia Medica) were published online on October 24, 2018 in Gastroenterology, an international authoritative journal of gastrointestinal disorders: Pseudokinase TRIB3 (Tribbles homolog 3) enhances the activity of Wnt/-catenin signaling pathway by interacting with the Wnt signaling pathway effectors, -catenin and TCF4 to form a heterotrimer, thus increasing and maintaining stem cell features of colon cancer stem cells and promoting the tumorigenesis, tumor development and resistance to chemotherapy drugs. This discovery provides a novel therapeutic concept and drug target for the treatment of colon cancer. Investigator Hu Zhuowei is the corresponding author of this paper, and the investigator Hua Fang and a doctoral candidate Shang Shuang were the co-first authors. Participants in this research also include a postgraduate Yang Yuwei. Professor Zhang Haizeng of a cancer hospital and his doctoral student Xu Tianlei have provided substantial support in clinical samples.

 

More recently, Hu Zhuowei’s research group has conducted a number of studies on the role and mechanism of pseudokinase protein TRIB3 in tumorigenesis and development. The research efforts of this group suggest that TRIB3 promotes the occurrence and development of leukemia, liver cancer, melanoma and other solid tumors by forming different protein-protein interaction complexes such as TRIB3–PML-RARa, TRIB3–SMAD3 and TRIB3–P62. The group’s efforts recently published in Gastroenterology found a positive correlation between TRIB3 and Wnt/-catenin, a key tumor-promoting signal related to colon cancer. By using the emergent 3D in vitro culture models of colon cancer organs and tumor spheres in recent years and in vivo models of frequency measurement of tumor stem cells, spontaneous colon cancer in ApcMin transgenic mice, colon cancer induced by carcinogenic inflammatory agent, etc., this group’s efforts further demonstrated that TRIB3 exerts its role in promoting the occurrence and development of colon cancer by forming a heterotrimer with -catenin/TCF4. On the basis of an elucidated molecular mechanism of TRIB3 in promoting colon cancer, the group’s investigators designed and obtained the lead compound that allows targeted bonding with -catenin in terms of protein interactions between -catenin and TRIB3. This primer removes the interaction between TRIB3 and -catenin, thereby inhibiting the formation of -catenin/TCF4 transcription complex, reducing its transcriptional activity, and reducing the expression level of TRIB3. Sufficient experimental evidence showed that the polypeptide not only significantly inhibites the growth of tumor-like organs derived from patients with colon cancer, but also reduces the propagation and migration of various colon cancer cell lines. It also showed good anticancer activity in various in vivo colon cancer models. Surprisingly, the polypeptide significantly increases the responsiveness of drug-resistant strain of colon cancer to chemotherapy drugs when used with the chemotherapy drug 5-fluorouracil.

 

 

 

Figure notes: TRIB3 forms a heterotrimer with -catenin and TCF4, and up-regulates the activity of Wnt/-catenin signaling pathway; -catenin can positively regulate the expression of TRIB3. The positive feedback regulation loop enhances the features of colon cancer stem cells and promotes the occurrence of colon cancer.

 

This study elucidated the molecular mechanism of colon cancer from a new view, and not only identified and discovered the potential new target of colon cancer treatment of the interaction between TRIB3 and -catenin-TCF4, but also developed therapeutic peptides targeted at this interaction, demonstrating the potential transformation from molecular mechanism research to clinical application. This research is mainly performed by the group of Professor Hu Zhuowei and financially supported by a number of Natural Science Foundation of China and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-007; 2016-I2M-3-008; 2016-I2M-1-011). At present, targeted protein-protein interaction is an emerging and hot field in drug research and development, and has shown great application prospect and potential economic value. This discovery provides new ideas and strategies for overcoming drug resistance in patients with colon cancer.

 

Paper link: https://doi.org/10.1053/j.gastro.2018.10.031

 

 

(Institute of Materia Medica)