Immunohistochemistry for Myc Predicts Survival in Colorectal Cancer

Toon, Christopher W.; Chou, Angela; Clarkson, Adele; DeSilva, Keshani; Houang, Michelle; Chan, Jason C. K.; Sioson, Loretta; Jankova, Lucy; Gill, Anthony J.

doi:10.1371/journal.pone.0087456

Cited by 35 publications

(34 citation statements)

References 15 publications

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“…While many downstream signaling molecules are affected by the combination therapy, MYC is a particularly important target. Overexpression of MYC is extensively documented in CRC and associated with poor survival (46). The Cancer Genome Atlas (TCGA) data indicate that MYC-dependent transcription is activated in nearly all CRC samples (1).…”

Section: Discussionmentioning

confidence: 99%

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer

Wang

Neitzel

et al. 2017

Clinical Cancer Research

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Purpose The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer (CRC). Experimental Design Using a panel of molecularly defined CRC cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches. Results BET inhibitors as monotherapy moderately reduced CRC cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized CRC cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo. A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous CRC xenografts. Conclusions Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in CRC and propose an effective combination strategy for the treatment of CRC.

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Section: Discussionmentioning

confidence: 99%

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer

Wang

Neitzel

et al. 2017

Clinical Cancer Research

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“…For statistical analysis, c-MYC and ß-catenin immunostaining were regarded as positive when they were expressed in more than 10 % of neoplastic nucleus in any intensity (Fig. 1 ) [ 19 , 28 ]. Negative controls were obtained omitting the primary antibody for each immunostaining.…”

Section: Methodsmentioning

confidence: 99%

“…Their prognostic value for CRC patients remains debatable. A recent study reported that c-MYC protein overexpression obtained by immunohistochemistry (IHC) was significantly correlated with better survival of CRC patients [ 19 ]. In contrast, other researchers conducted a meta-analysis showing that the accumulation of nuclear ß-catenin could be a biomarker for advanced stage and worse survival of CRC [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Favorable prognosis in colorectal cancer patients with co-expression of c-MYC and ß-catenin

et al. 2016

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BackgroundThe purpose of our research was to determine the prognostic impact and clinicopathological feature of c-MYC and β-catenin overexpression in colorectal cancer (CRC) patients.MethodsUsing immunohistochemistry (IHC), we measured the c-MYC and β-catenin expression in 367 consecutive CRC patients retrospectively (cohort 1). Also, c-MYC expression was measured by mRNA in situ hybridization. Moreover, to analyze regional heterogeneity, three sites of CRC including the primary, distant and lymph node metastasis were evaluated in 176 advanced CRC patients (cohort 2).ResultsIn cohort 1, c-MYC protein and mRNA overexpression and ß-catenin nuclear expression were found in 201 (54.8 %), 241 (65.7 %) and 221 (60.2 %) of 367 patients, respectively, each of which was associated with improved prognosis (P = 0.011, P = 0.012 and P = 0.033, respectively). Moreover, co-expression of c-MYC and ß-catenin was significantly correlated with longer survival by univariate (P = 0.012) and multivariate (P = 0.048) studies. Overexpression of c-MYC protein was associated with mRNA overexpression (ρ, 0.479; P < 0.001) and nuclear ß-catenin expression (ρ, 0.282; P < 0.001). Expression of c-MYC and ß-catenin was heterogeneous depending on location in advanced CRC patients (cohort 2). Nevertheless, both c-MYC and ß-catenin expression in primary cancer were significantly correlated with improved survival in univariate (P = 0.001) and multivariate (P = 0.002) analyses. c-MYC and ß-catenin expression of lymph node or distant metastatic tumor was not significantly correlated with patients’ prognosis (P > 0.05).ConclusionsCo-expression of c-MYC and ß-catenin was independently correlated with favorable prognosis in CRC patient. We concluded that the expression of c-MYC and ß-catenin might be useful predicting indicator of CRC patient’s prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2770-7) contains supplementary material, which is available to authorized users.

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“…The transcription factor c-Myc is commonly overexpressed in cancer 14,15 and regulates proliferation, differentiation, apoptosis, and epithelial-to-mesenchymal transition 16 . In mouse models of sporadic CRC, decreased c-Myc levels reduce Apc -driven tumorigenesis 17 .…”

Section: Introductionmentioning

confidence: 99%

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis

Parang

Kaz

Barrett

et al. 2016

Gut

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Objective Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumorigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function, and its relevance to inflammatory bowel disease (IBD) patients. Design We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with ulcerative colitis with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves−/− and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumor formation. Lastly, we utilized a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. Results BVES mRNA was reduced in tumors from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves−/− mice had increased tumor multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves−/− tumors revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signaling pathway whereby BVES interacts with PR61α, a PP2A regulatory subunit, to mediate c-Myc destruction. Conclusions Loss of BVES promotes inflammatory tumorigenesis through dysregulation of Wnt signaling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.

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Immunohistochemistry for Myc Predicts Survival in Colorectal Cancer

Cited by 35 publications

References 15 publications

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer

Favorable prognosis in colorectal cancer patients with co-expression of c-MYC and ß-catenin

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis

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