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TTPAL Promotes Colorectal Tumorigenesis

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TTPAL Promotes Colorectal Tumorigenesis Published OnlineFirst April 24, 2019; DOI: 10.1158/0008-5472.CAN-18-2986 Cancer Molecular Cell Biology Research TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/b-Catenin Signaling Hongyan Gou1,2, Jessie Qiaoyi Liang2, Lijing Zhang2, Huarong Chen2, Yanquan Zhang2, Rui Li2, Xiaohong Wang3, Jiafu Ji3, Joanna H. Tong4, Ka-Fai To4, Joseph J.Y. Sung2, Francis K.L. Chan2, Jing-Yuan Fang1, and Jun Yu2 Abstract Copy number alterations are crucial for the development of TTPAL. Depletion of TRIP6 significantly abolished the effects of colorectal cancer. Our whole-genome analysis identified TTPAL on cell proliferation and Wnt activation. Direct binding tocopherol alpha transfer protein-like (TTPAL) as preferentially of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitin- amplified in colorectal cancer. Here we demonstrate that fre- mediated degradation of TRIP6 and, subsequently, increased quent copy number gain of TTPAL leads to gene overexpression levels of TRIP6 displaced b-catenin from the tumor suppressor in colorectal cancer from a Chinese cohort (n ¼ 102), whichwas MAGI1 via competitive binding. This sequence of events allows further validated by a The Cancer Genome Atlas (TCGA) cohort b-catenin to enter the nucleus and promotes oncogenic Wnt/ (n ¼ 376). High expression of TTPAL was significantly associ- b-catenin signaling. In conclusion, TTPAL is commonly over- ated with shortened survival in patients with colorectal cancer. expressed in colorectal cancer due to copy number gain, which TTPAL promoted cell viability and clonogenicity, accelerated promotes colorectal tumorigenesis by activating Wnt/b-catenin cell-cycle progression, inhibited cell apoptosis, increased cell signaling via stabilization of TRIP6. TTPAL overexpression may migration/invasion ability in vitro, and promoted tumorigenic- serve as an independent new biomarker for the prognosis of ity and cancer metastasis in vivo. TTPAL significantly activated patients with colorectal cancer. Wnt signaling and increased b-catenin activation and protein expression of cyclin D1 and c-Myc. Coimmunoprecipitation Significance: TTPAL, a gene preferentially amplified in followed by mass spectrometry identified thyroid receptor– colorectal cancer, promotes colon tumorigenesis via activation interacting protein 6 (TRIP6) as a direct downstream effector of of the Wnt/b-catenin pathway. Introduction alterations (CNA) are common somatic changes in cancer fea- tured with gain or loss in copies of DNA sections (3). Deletions Colorectal cancer is the third most common cancer and the and copy number gains contribute to alterations in the expression second leading cause of cancer-related death worldwide (1, 2). of tumor suppressor genes and oncogenes, respectively. The The pathogenic mechanisms underlying colorectal cancer devel- stepwise accumulation of CNAs confers growth advantage and opment appear to be complex and heterogeneous. Copy number metastatic competence on cells, thus playing a crucial role in cancer initiation and progression. Recent studies have suggested that genes with CNAs are potential biomarkers and/or therapeutic 1Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenter- ology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes targets for colorectal cancer. Therefore, detection and mapping of and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, copy number abnormalities provide an approach for associating School of Medicine, Shanghai Jiaotong University, Shanghai, China. 2Institute aberrations with disease phenotype and for localizing critical of Digestive Disease and Department of Medicine and Therapeutics, State Key genes (4, 5). It is importance to identify and functionally char- Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK acterize novel genes with CNAs that are associated with colorectal Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong. 3 cancer (4). Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, fi China. 4Department of Anatomical and Cellular Pathology, State Key Laboratory Chromosome 20q ampli cation has been commonly found in of Oncology in South China, The Chinese University of Hong Kong, Hong Kong. colorectal cancer and is involved in transforming adenoma to carcinoma (5, 6). Chromosome 20q amplification is also a Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). potential indicator of poor prognosis in patients with colorectal cancer (7–9). By whole-genome sequencing (WGS), we identified H. Gou and J.Q. Liang are the co-first authors of this article. that TTPAL (tocopherol alpha transfer protein-like), located at Corresponding Author: Jun Yu, Institute of Digestive Disease and Department 20q13.12, was preferentially amplified in primary colorectal of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University tumor tissues. In keeping with our finding, analyses from The of Hong Kong, Hong Kong. Phone: 852-3763-6099; Fax: 852-2144-5330; E-mail: [email protected] Cancer Genome Atlas (TCGA) dataset showed that copy number gain of TTPAL occurs frequently in colorectal cancer and positively Cancer Res 2019;79:3332–46 correlates with its upregulated mRNA expression. Searching for doi: 10.1158/0008-5472.CAN-18-2986 the public protein datasets of Human Protein Altas, we found that Ó2019 American Association for Cancer Research. higher TTPAL protein expression was shown in colorectal cancer 3332 Cancer Res; 79(13) July 1, 2019 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst April 24, 2019; DOI: 10.1158/0008-5472.CAN-18-2986 Role of TTPAL in Colorectal Cancer tumor tissues compared with normal colon tissues from the PCR copy number analysis dataset DNA was extracted from 102 frozen colorectal cancer samples (http://www.proteinatlas.org). Moreover, high TTPAL mRNA of Chinese Cohort using the AllPrep DNA/RNA/Protein Kit expression is significantly associated with poor survival in (Qiagen). The purified genomic DNA was amplified with a probe patients with multiple cancer types (https://www.proteinatlas. specific to target gene TTPAL (Mm00082375_cn) by TaqMan org/ENSG00000124120-TTPAL/pathology#top; P < 0.001). Copy Number Assays (Applied Biosystems). The results were Therefore, we hypothesize that TTPAL plays an oncogenic func- analyzed by Copy Caller software v2.0 (Applied Biosystems). tion in colon carcinogenesis. The role of TTPAL in human cancer remains uninvestigated. In Subcutaneous xenograft and experimental metastasis mouse this study, we identified the frequent overexpression of TTPAL in models colorectal cancer due to its copy number gain. Further functional HCT116 and DLD1 cells stably transfected with TTPAL expression studies revealed that ectopic expression of TTPAL significantly vector or empty vector (5 Â 106 cells/0.1 mL PBS) were injected promoted colorectal cancer growth by enhancing G1–S cell-cycle subcutaneously into the left and right dorsal flanks of 4- to 6-week- progression and reducing apoptosis. The tumor-promoting effect old female Balb/c nude mice (n ¼ 8/group), respectively. Tumor size of TTPAL was revealed to be associated with the activation of Wnt/ was measured every 2 days for 2–3 weeks using a digital caliper. b-catenin signaling pathway by binding to thyroid receptor– Tumor volume (mm3) was estimated by measuring the longest and interacting protein 6 (TRIP6). The direct binding of TTPAL with shortest diameters of the tumor and calculating as described previ- TRIP6 in cytoplasm inhibited TRIP6 ubiquitin degradation. ously (10). At the endpoint, tumors were harvested and weighted. Enhanced cytoplasm TRIP6 displaced b-catenin from the tumor The excised tissues were either fixed in 10% neutral-buffered for- suppressor MAGI1 via competitive binding, which allowed malin or snap frozen in liquid nitrogen. Tumor sections from b-catenin to enter into the nucleus and subsequently activated paraffin-embedded blocks were used for histologic examination. the oncogenic Wnt/b-catenin signaling. Moreover, TTPAL over- For metastasis model, HCT116 cells stably transfected with expression was significantly associated with poor survival of TTPAL expression vector or empty vector (2 Â 106 cells in 0.1 mL patients with colorectal cancer. Thus, this study revealed a novel PBS) were injected intravenously via the tail vein (n ¼ 5). oncogenic mechanism and the clinical application value of TTPAL After 6–8 weeks, mice were sacrificed and their lungs were har- in colorectal cancer. vested. The lungs were sectioned and stained with hematoxylin and eosin. The number of lung metastases were counted. All experimental procedures were approved by the Animal Ethics Materials and Methods Committee of the Chinese University of Hong Kong. Colon cancer cell lines The colon cancer cell lines (DLD-1, HCT116, HT29, LOVO, Coimmunoprecipitation and liquid chromatography–mass SW480, RKO, and SW1116) were obtained from the ATCC spectrometry between 2014 and 2015 and cells' authentication were confirmed Coimmunoprecipitation (co-IP) assays were carried out as by short tandem repeat profiling. Cells were routinely cultured described previously (11, 12). Briefly, total protein from HCT116 and maintained in DMEM supplemented with 10% FBS and cells (5 Â 106/reaction) stably transfected with TTPAL (Flag- antibiotics (Gibco BRL) according to the ATCC
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