Role of the NF-κB signaling pathway in the pathogenesis of colorectal cancer

Soleimani, Atena; Rahmani, Farzad; Ferns, Gordon A.; Ryzhikov, Mikhail; Rezayi, Majid; Hassanian, Seyed Mahdi

doi:10.1016/j.gene.2019.144132

Cited by 164 publications

(126 citation statements)

References 78 publications

(43 reference statements)

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“…In our study, we revealed that elevated expression of G9a suppressed IκBαprotein and increased NF-κB luciferase activity, activating FAK signaling and promoting migration and invasion in NSCLCs. Similarly, recent study has demonstrated that NF-κB signaling pathway playsa very important role in oncogenesis and metastasis [47].NF-κBsignaling pathway has previously been shown to be associated with FAK activation and increased cell proliferation in lung cancer [48]. Tetraspanin 15 (TSPAN15) promoted esophageal cancer metastasis via activating NF-κB through regulating IκBαphosphorylation [49].In NSCLC, researchers have found that HMGB1mediated cancer cell motility is mediated in part by NF-κB-activated FAK signaling pathway [50].These and other studies demonstrate the importantrole of NF-κB in FAK signaling pathway and cancer metastasis and suggest thatNF-κB can also be considered as a potential druggable target in patients with G9a overexpressing lung cancers.…”

Section: Discussionmentioning

confidence: 93%

Histone Methyltransferase G9a Promotes Invasion of Non-small Cell Lung Cancer Through Enhancing Focaladhesionkinase Activationvia NF-KB Signaling Pathway

Sun¹,

Zhang²,

Pangeni³

et al. 2020

Preprint

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BackgroundOverexpression of euchromatic histone methyltransferase 2 (EHMT2 or G9a) is frequently found in a number of human cancers. Potential roles of G9a in invasion and metastasis are not well understood in non-small cell lung cancer (NSCLC). Here we investigated the effect and underlying mechanisms of G9a, and therapeutic implications of targeting G9a in the invasion of NSCLC. MethodsG9a-associated gene sets were identified by RNAseq analysis. Migration and invasion assays were applied to examine the impact of targeting G9a by siRNA knockdown orits specific inhibitor UNC0638 in NSCLC cells. Rescue experiments were designed to investigate the effect of focal adhesion kinase (FAK) and NF-κB inhibitors on the invasion of NSCLC cells overexpressing G9a. Correlation between the protein level of phosphorylated FAK and G9a was analyzed in NSCLC tissues.ResultsKnockdown and inhibition of G9a drastically suppressed in vitro cellular proliferation, migration, and invasion; while overexpression of G9a significantly enhanced proliferation, migration, and invasion of A549 and H1299 NSCLC cells. Targeting G9a led to a significant decrease in the expression of FAK protein and activation of FAK signaling pathway in both A549 and H1299 cells. Additionally, defactinib, a potent FAK inhibitor, partially abolished the enhanced migration and invasion by overexpression of G9a in these NSCLC cells. Furthermore, G9a was found to boost nuclear factor-kappa B (NF-κB) transcriptional activity in NSCLC cells through partially downregulating inhibitor of κB (IκBα), and an NF-κB inhibitor partially abolished the enhanced FAK activation by overexpressed G9a, which suggests that G9a-enhanced invasion and activation of FAK may be mediated by elevated NF-κB activity. Notably, a strong positive correlation between the immunohistochemical staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408).ConclusionsThese data strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.

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Section: Discussionmentioning

confidence: 93%

Histone Methyltransferase G9a Promotes Invasion of Non-small Cell Lung Cancer Through Enhancing Focaladhesionkinase Activationvia NF-KB Signaling Pathway

Sun¹,

Zhang²,

Pangeni³

et al. 2020

Preprint

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“…During the genesis and development of tumor, IKKβ phosphorylation increases, and further induces phosphorylation and ubiquitination of IκBα, which leads to the NF‐κB phosphorylation and separates from the complex of NF‐κB/IκBs. The free NF‐κB moves into the nucleus though the nuclear membrane and binds to its specific DNA sequence that induces high expression of the cell survival and antiapoptosis target genes of its downstream, and reduces the sensitivity of tumor cells to radiotherapy (DiDonato, Mercurio, & Karin, 2012; Mulero, Huxford, & Ghosh, 2019; Soleimani et al., 2019). Therefore, the inhibition of NF‐κB signaling pathway could enhance the radiosensitivity of tumor.…”

Section: Resultsmentioning

confidence: 99%

Allicin enhances the radiosensitivity of colorectal cancer cells via inhibition of NF‐κB signaling pathway

Huang

et al. 2020

Journal of Food Science

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Radioresistance is an important factor affecting the radiotherapy effect of colorectal cancer (CRC). Allicin is a versatile sulfur‐containing organic compound extracted from garlic (Allium sativum L.), which has many pharmacological effects. However, the effect of allicin on the sensitivity of CRC radiotherapy has not been confirmed. The present study is to observe the radiosensitivity effects of allicin and to explore its mechanism in CRC radiotherapy. The proliferation inhibition effects of allicin combined with X‐ray radiotherapy in HCT116 cells were measured by growth curve of cell and colony formation assays. The cell apoptosis was detected by Hoechst 33258 nucleus staining assay. The migration ability of cells was detected by Transwell chamber migration assay. The animal model of CRC was established in BALB/c mice via transplantation of CT26 cell, and the radiosensitization effect of allicin on CRC was detected in vivo. The mRNA expressions of NF‐κB, IKKβ, and IκBα were analyzed by reverse transcription‐polymerase chain reaction (RT‐PCR). The protein expressions of NF‐κB, p‐NF‐κB, IKKβ, p‐IKKβ, IκBα, and p‐IκBα were detected by western blotting. Our results showed that allicin improves the sensitivity of X‐ray radiotherapy in CRC, and its mechanism may be associated with inhibition of NF‐κB signaling pathway. These findings suggest that allicin may be used as a potential sensitizer for tumor radiotherapy in the clinic.

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“…A number of studies found that NF-κB signaling pathway plays highly important roles in cell proliferation, apoptosis, angiogenesis, in ammation, metastasis, and drug resistance. [23][24][25] A variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs. 26 In this study, the protein expression of P65, IκBα, and their phosphorylated were detected by western blot.…”

Section: Discussionmentioning

confidence: 99%

MiR-381 enhances the sensitivity of non-small cell lung cancer to radiotherapy by targeting ROCK2 to regulate NF-κB signaling pathway

Huang

Zeng

Zhang

et al. 2020

Preprint

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BackgroundWe investigated the effect of miR-381 on the sensitivity of non-small cell lung cancer (NSCLC) to radiotherapy, and examined its possible mechanism.MethodsNSCLC A549 cells and miR-381 overexpression and gene silencing cell lines were treated with radiotherapy. The cell proliferation was tested by CCK-8 assay and colony formation. Flow cytometry and TUNEL were used to detect the cell apoptosis. The expression of nuclear factor kappa B (NF-κB) signaling pathway related proteins were detected by western blot. NF-κB signaling pathway activator and inhibitor cell lines were further constructed and the above experiments were repeated. Double luciferase assay was used to verify the target of miR-381. Furthermore, a nude mouse xenograft model was constructed and treated with radiotherapy. The tumor volume and tumor weight were measured. The expression of PCNA protein in tumor tissues was observed by immunohistochemistry. The apoptosis related proteins in tumor tissues were detected by western blot.ResultsThe mRNA expression of miR-381 was increased after radiotherapy treatment. Radiotherapy treatment also can inhibit the proliferation and promote apoptosis of A549 cells. Compared with radiotherapy group, cell proliferation was significantly decreased and apoptosis was significantly increased in miR-381 overexpression group (p < 0.05). Moreover, ROCK2 is a target of miR-381, and overexpression of miR-381 can down-regulate the expression of ROCK2 protein. In nude mice, miR-381 mimic interference can reduce cell tumorigenicity and proliferation, and increase the apoptosis. However, the indicators above were contrary in miR-381 silencing group. Verification experiments further verify that NF-κB signaling pathway activator can reverse the role of miR-381.ConclusionMiR-381 overexpression could enhance the sensitivity of NSCLC to radiotherapy by targeting ROCK2 to inhibit NF-κB signaling pathway.

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Role of the NF-κB signaling pathway in the pathogenesis of colorectal cancer

Cited by 164 publications

References 78 publications

Histone Methyltransferase G9a Promotes Invasion of Non-small Cell Lung Cancer Through Enhancing Focaladhesionkinase Activationvia NF-KB Signaling Pathway

Histone Methyltransferase G9a Promotes Invasion of Non-small Cell Lung Cancer Through Enhancing Focaladhesionkinase Activationvia NF-KB Signaling Pathway

Allicin enhances the radiosensitivity of colorectal cancer cells via inhibition of NF‐κB signaling pathway

MiR-381 enhances the sensitivity of non-small cell lung cancer to radiotherapy by targeting ROCK2 to regulate NF-κB signaling pathway

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