BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies hav...BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.展开更多
跨膜蛋白176B(transmembrane protein 176b,TMEM176B),最初称为TORID,是一种具有4个潜在跨膜结构域的主要表达于淋巴组织的跨膜蛋白。在树突状细胞的成熟、抗原交叉呈递以及肿瘤细胞的行为中发挥调节作用,并且影响移植物抗宿主病、神经...跨膜蛋白176B(transmembrane protein 176b,TMEM176B),最初称为TORID,是一种具有4个潜在跨膜结构域的主要表达于淋巴组织的跨膜蛋白。在树突状细胞的成熟、抗原交叉呈递以及肿瘤细胞的行为中发挥调节作用,并且影响移植物抗宿主病、神经系统疾病和肿瘤等疾病的发生和发展。本文就TMEM176B的结构、定位、生物学功能及其在疾病中的作用进行综述,以期为后续研究TMEM176B的功能及相关疾病的干预提供参考。展开更多
As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneou...As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.展开更多
基金Ministry of Education Industry-University Co-operation Collaborative Education Project,No.202102242020.
文摘BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.
文摘跨膜蛋白176B(transmembrane protein 176b,TMEM176B),最初称为TORID,是一种具有4个潜在跨膜结构域的主要表达于淋巴组织的跨膜蛋白。在树突状细胞的成熟、抗原交叉呈递以及肿瘤细胞的行为中发挥调节作用,并且影响移植物抗宿主病、神经系统疾病和肿瘤等疾病的发生和发展。本文就TMEM176B的结构、定位、生物学功能及其在疾病中的作用进行综述,以期为后续研究TMEM176B的功能及相关疾病的干预提供参考。
基金supported in part by grants from the Beijing Natural Science Foundation of China(Grant No.7192123,7222117)the National Natural Science Foundation of China(Grant No.31770793,82000812)the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.2018122).
文摘As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.
