c-Myb regulates NOX1/p38 to control survival of colorectal carcinoma cells

Pekarčíková, Lucie; Knopfová, Lucia; Beneš, Petr; Šmarda, Jan

doi:10.1016/j.cellsig.2016.04.007

Cited by 22 publications

(18 citation statements)

References 67 publications

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“…2a ) and tissues (TCGA database) (Fig. 2b ), which is consistent with previous research 20 . Then, HCT116 and HT29 cell lines were transfected with c-Myb siRNA, NC siRNA, Vector, and c-Myb, respectively.…”

Section: Resultssupporting

confidence: 92%

RETRACTED ARTICLE: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7

et al. 2018

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Mounting evidences indicate that circular RNAs (circRNAs) have a vital role in human diseases, especially cancers. More recently, circHIPK3, a particularly abundant circRNA, was proposed to be involved in tumorigenesis. However, its role in colorectal cancer (CRC) has not been explored. In this study, we found circHIPK3 was significantly upregulated in CRC tissues and cell lines, at least in part, due to c-Myb overexpression and positively correlated with metastasis and advanced clinical stage. Moreover, Cox multivariate survival analysis showed that high-level expression of circHIPK3 was an independent prognostic factor of poor overall survival (OS) in CRC (hazard ratio [HR] = 2.75, 95% confidence interval [CI] 1.74–6.51, p = 0.009). Functionally, knockdown of circHIPK3 markedly inhibited CRC cells proliferation, migration, invasion, and induced apoptosis in vitro and suppressed CRC growth and metastasis in vivo. Mechanistically, by using biotinylated-circHIPK3 probe to perform RNA pull-down assay in CRC cells, we identified miR-7 was the only one microRNA that was abundantly pulled down by circHIPK3 in both HCT116 and HT29 cells and these interactions were also confirmed by biotinylated miR-7 pull-down and dual-luciferase reporter assays. Overexpression of miR-7 mimicked the effect of circHIPK3 knockdown on CRC cells proliferation, migration, invasion, and apoptosis. Furthermore, ectopic expression of circHIPK3 effectively reversed miR-7-induced attenuation of malignant phenotypes of CRC cells by increasing the expression levels of miR-7 targeting proto-oncogenes (FAK, IGF1R, EGFR, YY1). Remarkably, the combination of circHIPK3 silencing and miR-7 overexpression gave a better effect on tumor suppression both in vitro and in vivo than did circHIPK3 knockdown or miR-7 overexpression alone. Taken together, our data indicate that circHIPK3 may have considerable potential as a prognostic biomarker in CRC, and support the notion that therapeutic targeting of the c-Myb/circHIPK3/miR-7 axis may be a promising treatment approach for CRC patients.

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Section: Resultssupporting

confidence: 92%

RETRACTED ARTICLE: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7

et al. 2018

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“…Finally, we confirmed with the PathScan array that p38 MAPK activity was increased in resistant cells compared to sensitive cells. Several publications have highlighted the connection existing between the ROS produced by Nox1 and the activation of p38 MAPK [ 32 ]. We have observed that p38 MAPK was strongly phosphorylated and thus activated in our resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Reversion of resistance to oxaliplatin by inhibition of p38 MAPK in colorectal cancer cell lines: involvement of the calpain / Nox1 pathway

2017

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Oxaliplatin is a major treatment for metastatic colorectal cancer, however its effectiveness is greatly diminished by the development of resistances. Our previous work has shown that oxaliplatin efficacy depends on the reactive oxygen species (ROS) produced by Nox1. In this report, we investigated Nox1 involvement in the survival mechanisms of oxaliplatin resistant cell lines that we have selected. Our results show that basal ROS production by Nox1 is increased in resistant cells. Whereas the transitory Nox1-dependent production of superoxide contributes to the cytotoxicity of oxaliplatin in sensitive cells, oxaliplatin treatment of resistant cells leads to a decrease in the production of superoxide associated with an increase of H2O2 and a decreased cytotoxicity of oxaliplatin. We have shown that calpains regulate differently Nox1 according to the sensitivity of the cells to oxaliplatin. In sensitive cells, calpains inhibit Nox1 by cleaving NoxA1 leading to a transient ROS production necessary for oxaliplatin cytotoxic effects. In contrast, in resistant cells calpain activation is associated with an increase of Nox1 activity through Src kinases, inducing a strong and maintained ROS production responsible for cell survival. Using a kinomic study we have shown that this overactivation of Nox1 results in an increase of p38 MAPK activity allowing the resistant cells to escape apoptosis. Our results show that the modulation of Nox1 activity in the context of anticancer treatment remains complex. However, a strategy to maximize Nox1 activation while inhibiting the p38 MAPK-dependent escape routes appears to be an option of choice to optimize oxaliplatin efficiency.

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“…Second, as c-Myb is considered to act as a driver of cancer cell proliferative growth, Hugo et al suggested that non-quiescent, actively cycling (c-Myb-positive) tumor cells could be more amenable to treatment with cytotoxic drugs targeting highly proliferating cells 23. As we and others previously reported that high c-Myb expression in CRC cell lines enhanced their chemorezistance 24-26, the „metastasis hypothesis“ seems to be more relevant. It should be noted, however, that high c-Myb protein level was associated with poor prognosis in gallbladder adenocarcinoma 27, 28 and esophageal squamous cell carcinoma 29 and two previous studies by Ramsay group reported that high c-Myb associates with poor prognosis in CRC patients 30, 31.…”

Section: Discussionmentioning

confidence: 70%

High c-Myb Expression Associates with Good Prognosis in Colorectal Carcinoma

et al. 2019

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Colorectal cancer (CRC) represents a serious challenge for oncologists due to high incidence and large heterogeneity. Prognostic factors are needed to stratify patients according to risk of disease progression. In this study, we report that high expression of c-Myb protein, determined by immunohistochemistry (IHC), associates with better overall and disease-free survival (OS, DFS) in a cohort of 103 patients. Although MYB has been previously considered to act as oncogene in CRC, our further analysis of datasets deposited in PrognoScan and SurvExpress databases confirmed that high MYB expression largely associates with good prognosis in CRC. As therapies targeting c-Myb have been developed and tested in preclinical studies, we believe that further studies are needed for detailed understanding of c-Myb function in CRC, before the c-Myb-targeted therapy enters clinical trials.

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c-Myb regulates NOX1/p38 to control survival of colorectal carcinoma cells

Cited by 22 publications

References 67 publications

RETRACTED ARTICLE: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7

RETRACTED ARTICLE: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7

Reversion of resistance to oxaliplatin by inhibition of p38 MAPK in colorectal cancer cell lines: involvement of the calpain / Nox1 pathway

High c-Myb Expression Associates with Good Prognosis in Colorectal Carcinoma

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