VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer

• Published in: International journal of cancer 2020-01, Vol.146 (2), p.496-509
• Main Authors: Chen, Yiyu, Liu, Zhen, Wang, Huijun, Tang, Zibo, Liu, Yiyi, Liang, Zixi, Deng, Xiaojie, Zhao, Mengyang, Fu, Qiaofen, Li, Libo, Cai, Hongbing, Xie, Weibing, Fang, Weiyi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal models; Animals; Azoxymethane; Cancer; Carcinogens; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Cell Proliferation - genetics; chemical carcinogens; Chemoresistance; Cisplatin; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Cytoplasm; Cytoskeletal Proteins - genetics; Dextran; Dextran sulfate; Down-Regulation - drug effects; Down-Regulation - genetics; EGFR/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; Feedback; Feedback loops; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genes, Tumor Suppressor - drug effects; HT29 Cells; Humans; Medical research; Metastases; Mice; Myc protein; NESG1; Nicotine; Nicotine - pharmacology; p53 Protein; Phenotypes; Protein transport; Reversion; Signal Transduction - drug effects; Signal Transduction - genetics; Transcription; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Tumor suppressor genes; Vesicular Transport Proteins - genetics; VPS33B
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32429

The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) ‐induced CRC mice models and nicotine‐treated CRC cells via the PI3K/AKT/c‐Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop and the downstream cell cycle or EMT‐related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c‐Jun‐mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c‐Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B‐modulating signal in VPS33B‐overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop and thus suppress the malignant phenotype of CRC. What's new? Vacuolar protein sorting 33B (VPS33B) has been suggested to serve as an important tumor suppressor in hepatocarcinogenesis. Here, the authors show that VPS33B is downregulated by chemical carcinogens and poorly expressed in colorectal cancer (CRC) tissues. CRC patients with higher expression of VPS33B have a longer survival time. Furthermore, they demonstrate that VPS33B can interact with NESG1 to suppress cell proliferation, invasion, migration, and intrahepatic metastasis and increase sensitivity to cisplatin via regulating the EGFR/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop. The data provide novel insight into the significance of VPS33B in CRC and may pave the way for a new treatment strategy.