TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

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Abstract

Colorectal carcinoma (CRC) is a malignant epithelial tumour with tremendous invasion and metastatic capacity. Transforming acidic coiled-coil protein-3 (TACC3), a frequently aberrantly expressed oncogene, is an important biomarker in various human cancers. Our study aimed to investigate the expression and function of TACC3 in human CRC. We found that TACC3 was over-expressed at both the mRNA and protein levels in CRC cells and in biopsies of CRC tissues compared with normal controls as determined by qRT-PCR, western blot and immunohistochemical (IHC) staining assays. IHC staining of samples from 161 patients with CRC also revealed that TACC3 expression was significantly correlated with clinical stage ( P = 0.045), T classification ( P = 0.029) and M classification ( P = 0.020). Multivariate analysis indicated that high TACC3 expression was an independent prognostic marker for CRC. Patients who had high TACC3 expression had significantly poorer overall survival (OS, P = 0.023) and disease-free survival (DFS, P = 0.019) compared to patients who had low TACC3 expression. Furthermore, TACC3 knockdown attenuated CRC cell proliferation, colony formation capability, migration and invasion capability, and tumourigenesis in nude mice; these properties were measured using a real-time cell analyser (RTCA), clonogenicity analysis, and transwell and xenograft assays, respectively. These data indicate that TACC3 promotes CRC progression and could be an independent prognostic factor and a potential therapeutic target for CRC.

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Most cited references 23

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CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.

Shuji Ogino, Katsuhiko Nosho, Gregory Kirkner … (2009)

The CpG island methylator phenotype (CIMP), characterised by widespread promoter methylation, is associated with microsatellite instability (MSI) and BRAF mutation in colorectal cancer. The independent effect of CIMP, MSI and BRAF mutation on prognosis remains uncertain. Utilising 649 colon cancers (stage I-IV) in two independent cohort studies, we quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) as well as CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN by using MethyLight technology. We examined MSI, KRAS and BRAF status. Cox proportional hazard models computed hazard ratios (HRs) for colon cancer-specific and overall mortalities, adjusting for patient characteristics and tumoral molecular features. After adjustment for other predictors of patient survival, patients with CIMP-high cancers (126 (19%) tumours with >or=6/8 methylated CIMP-specific promoters) experienced a significantly low colon cancer-specific mortality (multivariate HR 0.44, 95% confidence interval (CI) 0.22 to 0.88), whereas the BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI 1.13 to 3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumours (multivariate HR 0.70, 95% CI 0.36 to 1.37). In stratified analyses, CIMP-high tumours were associated with a significant reduction in colon cancer-specific mortality, regardless of both MSI and BRAF status. The relation between CIMP-high and lower mortality appeared to be consistent across all stages. KRAS mutation was unrelated to prognostic significance. CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality.

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The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma.

Olli Yli-Harja, Ping Ji, Gregory Fuller … (2013)

Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Fusions can lead to production of oncogenic fusion proteins or to enhanced expression of oncogenes. Several recent studies have reported that some fusion genes can escape microRNA regulation via 3'-untranslated region (3'-UTR) deletion. We performed whole transcriptome sequencing to identify fusion genes in glioma and discovered FGFR3-TACC3 fusions in 4 of 48 glioblastoma samples from patients both of mixed European and of Asian descent, but not in any of 43 low-grade glioma samples tested. The fusion, caused by tandem duplication on 4p16.3, led to the loss of the 3'-UTR of FGFR3, blocking gene regulation of miR-99a and enhancing expression of the fusion gene. The fusion gene was mutually exclusive with EGFR, PDGFR, or MET amplification. Using cultured glioblastoma cells and a mouse xenograft model, we found that fusion protein expression promoted cell proliferation and tumor progression, while WT FGFR3 protein was not tumorigenic, even under forced overexpression. These results demonstrated that the FGFR3-TACC3 gene fusion is expressed in human cancer and generates an oncogenic protein that promotes tumorigenesis in glioblastoma.

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KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803.

J Mayer, Jeffrey P Schaefer, Donna Niedzwiecki … (2009)

Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy (cetuximab or panitumumab). It remains uncertain, however, whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy. We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999-2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/node stage, performance status, adjuvant chemotherapy arm, and microsatellite instability status. Compared with patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free, recurrence-free, or overall survival. The 5-year disease-free, recurrence-free, and overall survival rates (KRAS-mutated versus KRAS-wild-type patients) were 62% versus 63% (log-rank P = 0.89), 64% versus 66% (P = 0.84), and 75% versus 73% (P = 0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm, or microsatellite instability status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 5 July 2016

Publication date (Electronic): 26 May 2016

Volume: 7

Issue: 27

Pages: 41885-41897

Affiliations

¹ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

² State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

³ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Departments of Pathology and Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

⁴ Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

⁵ Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China

⁶ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

⁷ Department of Emergency, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China

⁸ Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

⁹ Current affiliation: Japan Agency for Medical Research and Development (AMED), Tokyo, Japan

Author notes

Correspondence to: Huanliang Liu, liuhuanl@ 123456mail.sysu.edu.cn

Xing Zhang, zhangxing@ 123456sysucc.org.cn

Article

Publisher ID: 9628

DOI: 10.18632/oncotarget.9628

PMC ID: 5173103

PubMed ID: 27248823

SO-VID: 805c9e5e-8077-42e9-97ab-b13ae256815b

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

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Karger: Oncology

Most cited references 23

CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.

The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma.

KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803.

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