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      The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer

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          Abstract

          The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in KRAS-wild-type ( KRAS -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells, as already confirmed in KRAS-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models. Kaplan-Meier and Cox regression analysis indicated that DDX3, KRAS, and YAP1 expression had prognostic value for OS and RFS in KRAS-WT and KRAS-mutated tumors, but SIX2 and YAP1/SIX2 were prognostic value only in KRAS-WT patients. The observation from patients seemed to support the mechanistic action of cell and animal models. We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3-mediated tumor aggressiveness and enhance CTX sensitivity in KRAS-WT colorectal cancer.

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          Worldwide variations in colorectal cancer.

          Melissa M Center, Ahmedin Jemal, Robert A Smith … (2009)
          Previous studies have documented significant international variations in colorectal cancer rates. However, these studies were limited because they were based on old data or examined only incidence or mortality data. In this article, the colorectal cancer burden and patterns worldwide are described using the most recently updated cancer incidence and mortality data available from the International Agency for Research on Cancer (IARC). The authors provide 5-year (1998-2002), age-standardized colorectal cancer incidence rates for select cancer registries in IARC's Cancer Incidence in Five Continents, and trends in age-standardized death rates by single calendar year for select countries in the World Health Organization mortality database. In addition, available information regarding worldwide colorectal cancer screening initiatives are presented. The highest colorectal cancer incidence rates in 1998-2002 were observed in registries from North America, Oceania, and Europe, including Eastern European countries. These high rates are most likely the result of increases in risk factors associated with "Westernization," such as obesity and physical inactivity. In contrast, the lowest colorectal cancer incidence rates were observed from registries in Asia, Africa, and South America. Colorectal cancer mortality rates have declined in many longstanding as well as newly economically developed countries; however, they continue to increase in some low-resource countries of South America and Eastern Europe. Various screening options for colorectal cancer are available and further international consideration of targeted screening programs and/or recommendations could help alleviate the burden of colorectal cancer worldwide.
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            PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients.

            F Perrone, A Lampis, M Orsenigo … (2009)
            It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.
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              Extracellular matrix protein betaig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation.

              Shideng Bao, Chaoyu Ma, Daniel Radiloff … (2008)
              Metastasis, the major cause of cancer death, is a multistep process that requires interactions between cancer cells and stromal cells and between cancer cells and extracellular matrix. Molecular alterations of the extracellular matrix in the tumor microenvironment have a considerable impact on the metastatic process during tumorigenesis. Here we report that elevated expression of betaig-h3/TGFBI (transforming growth factor, beta-induced), an extracellular matrix protein secreted by colon cancer cells, is associated with high-grade human colon cancers. Ectopic expression of the betaig-h3 protein enhanced the aggressiveness and altered the metastatic properties of colon cancer cells in vivo. Inhibition of betaig-h3 expression dramatically reduced metastasis. Mechanistically, betaig-h3 appears to promote extravasation, a critical step in the metastatic dissemination of cancer cells, by inducing the dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin alphavbeta5-Src signaling pathway. Thus, cancers associated with overexpression of betaig-h3 may have an increased metastatic potential, leading to poor prognosis in cancer patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Theranostics
                Journal ID (iso-abbrev): Theranostics
                Journal ID (publisher-id): thno
                Title: Theranostics
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1838-7640
                Publication date Collection: 2017
                Publication date (Electronic): 27 February 2017
                Volume: 7
                Issue: 5
                Pages: 1114-1132
                Affiliations
                [1 ]Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
                [2 ]Department of Public Health, Chung Shan Medical University, Taichung, Taiwan
                [3 ]Department of Surgery, Chung Shan Medical University, Taichung, Taiwan
                Author notes
                ✉ Corresponding author: Huei Lee, Ph. D., Professor, Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Room 5, 12 th floor, F building, No. 3, Park Street, Nangang District 115, Taipei, Taiwan. Tel: 886-27361661 ext. 7616; Fax: 886-26558562; E-mail: hl@ 123456tmu.edu.tw

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: thnov07p1114
                DOI: 10.7150/thno.18175
                PMC ID: 5399580
                PubMed ID: 28435452
                SO-VID: c4f4a886-e826-4f8a-9936-cee77b60aab6
                Copyright © ©Ivyspring International Publisher
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 1 November 2016
                Date accepted : 4 January 2017
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Molecular medicine
                Keywords: ddx3,yap1,six2,kras,and colorectal cancer.
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: ddx3, yap1, six2, kras, and colorectal cancer.

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