Zhao-Liang Yu1,2, Yu-Feng Chen1,2, Feng Gao3,4, Xiao-Jian Wu5,6,7, Bin Zheng2,8, Ze-Rong Cai1,2, Yi-Feng Zou1,2, Jia Ke1,2, Ping Lan1,2,8. 1. Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. 2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China. 3. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China. gaof57@mail.sysu.edu.cn. 4. Guangdong Institute of Gastroenterology, Guangzhou, China. gaof57@mail.sysu.edu.cn. 5. Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. wuxjian@mail.sysu.edu.cn. 6. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China. wuxjian@mail.sysu.edu.cn. 7. Guangdong Institute of Gastroenterology, Guangzhou, China. wuxjian@mail.sysu.edu.cn. 8. Guangdong Institute of Gastroenterology, Guangzhou, China.
Abstract
BACKGROUND: Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS: Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS: By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/β-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION: Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).
BACKGROUND:Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS: Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS: By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/β-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION: Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).
Entities:
Keywords:
Cancer stem cell; Chemoresistance; Colorectal cancer; Protein–protein interaction; TMEM17
Authors: Julien Taieb; Hampig Raphael Kourie; Jean-François Emile; Karine Le Malicot; Ralyath Balogoun; Josep Tabernero; Enrico Mini; Gunnar Folprecht; Jean-Luc Van Laethem; Claire Mulot; Olivier Bouché; Thomas Aparicio; Pierre Michel; Josef Thaler; John Bridgewater; Eric Van Cutsem; Géraldine Perkins; Come Lepage; Ramon Salazar; Pierre Laurent-Puig Journal: JAMA Oncol Date: 2018-07-12 Impact factor: 31.777
Authors: Sébastien Marx; Thomas Dal Maso; Jia-Wei Chen; Marina Bury; Johan Wouters; Carine Michiels; Benjamin Le Calvé Journal: Semin Cancer Biol Date: 2019-08-24 Impact factor: 15.707
Authors: Felipe de Sousa e Melo; Antonina V Kurtova; Jonathan M Harnoss; Noelyn Kljavin; Joerg D Hoeck; Jeffrey Hung; Jeffrey Eastham Anderson; Elaine E Storm; Zora Modrusan; Hartmut Koeppen; Gerrit J P Dijkgraaf; Robert Piskol; Frederic J de Sauvage Journal: Nature Date: 2017-03-29 Impact factor: 49.962
Authors: Jose J G Marin; Fermin Sanchez de Medina; Beatriz Castaño; Luis Bujanda; Marta R Romero; Olga Martinez-Augustin; Rosario Del Moral-Avila; Oscar Briz Journal: Drug Metab Rev Date: 2012-05 Impact factor: 4.518
Authors: D D Fang; Y J Kim; C N Lee; S Aggarwal; K McKinnon; D Mesmer; J Norton; C E Birse; T He; S M Ruben; P A Moore Journal: Br J Cancer Date: 2010-03-23 Impact factor: 7.640
Authors: L Vermeulen; M Todaro; F de Sousa Mello; M R Sprick; K Kemper; M Perez Alea; D J Richel; G Stassi; J P Medema Journal: Proc Natl Acad Sci U S A Date: 2008-09-02 Impact factor: 11.205
Authors: Piero Dalerba; Scott J Dylla; In-Kyung Park; Rui Liu; Xinhao Wang; Robert W Cho; Timothy Hoey; Austin Gurney; Emina H Huang; Diane M Simeone; Andrew A Shelton; Giorgio Parmiani; Chiara Castelli; Michael F Clarke Journal: Proc Natl Acad Sci U S A Date: 2007-06-04 Impact factor: 11.205