High expression levels of nuclear factor kappa B and gelatinases in the tumorigenesis of oral squamous cell carcinoma

Sukumaran, Bindhu Omana; Ramadas, K; Stolzmann, Paul; Pillai, M. Radhakrishna

doi:10.1002/hed.20437

Cited by 65 publications

(59 citation statements)

References 39 publications

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“…Immunolocalization of p65 was evident in the nucleus and the cytoplasm of renal cell tumors, while normal cells displayed predominantly cytoplasmic immunolocalization, with rare and very weak nuclear immunoreactivity. This observation suggests that p65 nuclear translocation may be an important event during malignant transformation, as previously suggested (23).…”

Section: Discussionsupporting

confidence: 80%

Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-κB in Renal Cell Tumors

et al. 2008

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Aim To assess the relationship between protein and messenger RNA (mRNA) levels of vascular endothelial growth factor (VEGF) and subcellular localization of nuclear factor-kappa B (NF-κB), proliferation rate of tumor cells, and clinicopathological characteristics of renal cell tumors.Methods We analyzed 31 one renal cell tumors -22 clear cell renal cell carcinomas (CCRCC) and 9 other histologic types (non-CCRCC). VEGF expression and subcellular localization of p65 member of NF-κB and Ki67 were immunohistochemically evaluated for the proliferation rate of tumor cells. Expression of VEGF mRNA was assessed using quantitative real-time polymerase chain reaction after total RNA extraction from snap-frozen tumor tissue samples.Results Cytoplasmic localization of VEGF protein in renal cell tumors showed a perimembranous and diffuse pattern, the former being more evident in CCRCC (27.1 ± 18.9 vs 3.3 ± 10 % tumors, P<0.001) and the latter in non-CCRCC type (71.7 ± 23.2 vs 31.1 ± 22.1 % tumors, P < 0.001). Heterogeneity in VEGF gene expression was more pronounced in CCRCC type than in non-CCRCC type (P = 0.004). In addition, perimembranous VEGF pattern was associated with higher VEGF mRNA levels (P = 0.006) and diffuse VEGF pattern with lower VEGF mRNA levels (P < 0.001). Nuclear and cytoplasmic staining of NF-κB/ p65 was observed in the majority of tumor cells. A significant association was recorded between cytoplasmic NK-κB/65 staining and VEGF staining of diffuse pattern (P = 0.026). Association between NF-κB/65 and proliferation rate of tumor cells was significant for cytoplasmic staining (P = 0.039) but not for nuclear NFkB/p65 staining (P = 0.099). ConclusionHigher but inhomogeneous expression of VEGF in tumor cells, especially in CCRCCs, is associated with NF-κB/65 activity. This indicates that both VEGF and NF-κB/65 may be important in renal carcinogenesis, representing a possible molecular target in the treatment of renal cell carcinoma.

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Section: Discussionsupporting

confidence: 80%

Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-κB in Renal Cell Tumors

et al. 2008

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“…While our study was under review another laboratory also reported gradual increase in the nuclear translocation and intensity of NFjB expression in OSCCs. 27 Furthermore, in our study a correlation was observed between the expression of NF-jB and COX-2 proteins in OPLs; these proteins showed sustained elevation and correlation in OSCCs as well. The significant increase in expression of NF-jB and COX-2 from normal to OPLs to OSCCs suggests their association with development and progression of oral cancer.…”

Section: Discussionsupporting

confidence: 62%

Expression of NF‐κB parallels COX‐2 expression in oral precancer and cancer: Association with smokeless tobacco

Sawhney

Rohatgi

Kaur

et al. 2007

Intl Journal of Cancer

114

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Nuclear Factor‐κB (NF‐κB) activation and COX‐2 overexpression have been reported in head and neck cancer, but the relationship between these proteins remains to be investigated. To determine the relationship between NF‐κB and COX‐2 in Smokeless Tobacco (ST) associated oral tumorigenesis, we performed immunohistochemistry in serial sections from 107 OSCCs, 78 oral precancerous lesions (OPLs) (58 hyperplasias, 20 dysplasias) and 15 histologically normal oral tissues and correlated with clinicopathological data. Significant increase in NF‐κB and COX‐2 immunopositivity was observed from normal oral mucosa to OPLs to OSCCs (p = 0.009 and p = 0.002 respectively). Upregulation of NF‐κB and COX‐2 was observed as early as in hyperplasia [p = 0.006; OR = 6.1 and p = 0.003; OR = 7.6, respectively]. Expression of both proteins was found to be significantly associated in OPLs (p = 0.000; OR = 12.6) and OSCCs (p = 0.001; OR = 4.0). Intriguingly, khaini consumption correlated with NF‐κB immunopositivity in OPLs (p = 0.05, OR = 3.8) and OSCCs (p = 0.01, OR = 3.4) and with COX‐2 expression in OPLs (p = 0.03; OR = 4.3). In vitro experimental system of ST associated oral carcinogenesis was used to demonstrate ST (khaini) and NNK mediated activation of NF‐κB and COX‐2, supporting the clinical data. In conclusion, this study demonstrates correlation between over expression of NF‐κB and COX‐2 in early precancerous stages of development of oral cancer and sustained elevation down the tumorigenic pathway, underscoring their potential as targets for early intervention. In vitro studies demonstrated that NNK may be one of the carcinogenic components of ST (khaini) inducing activation of NF‐κB and COX‐2 in oral precancer and cancer cells, suggesting plausible role in ST‐induced oral carcinogenesis. © 2007 Wiley‐Liss, Inc.

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“…Yan et al and Bindhu et al provided evidences that the nuclear translocation of NF-kB (p50-p65) gradually progresses from the premalignant phase of oral tissue to the invasive phase. 13,30 Given that the NF-kB pool that translocates to the nucleus is the phosphorylated fraction, 31,32 the observed increase indirectly demonstrates activation of the NF-kB mediated signaling. Additionally, significant increase in pAkt S473 , a regulator of NF-kB, compared to the unaltered total protein in MIEN1 overexpressing DOK cells confirms that the Akt/NF-kB signaling axis is exploited by MIEN1 to induce expression of MMP-9.…”

Section: Discussionmentioning

confidence: 99%

MIEN1 promotes oral cancer progression and implicates poor overall survival

Rajendiran

Kpetemey

Maji

et al. 2015

Cancer Biology & Therapy

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Abbreviations: CRS, current reformed smoker; CS, current smoker; GFP, green fluorescent protein; HNSCC, head and neck squamous cell carcinoma; MIEN1, migration and invasion enhancer 1; MMP-9, matrix metallopeptidase 9; NF-kB, nuclear factor kappalight-chain-enhancer of activated B cells; OSCC, oral squamous cell carcinoma; siRNA, small interfering RNA; TCGA, the cancer genome atlas; uPA, urokinase plasminogen activator; VEGF, vascular endothelial growth factorOral squamous cell carcinoma is a highly malignant tumor with the potential to invade local and distant sites and promote lymph node metastasis. Major players underlying the molecular mechanisms behind tumor progression are yet to be fully explored. Migration and invasion enhancer 1 (MIEN1), a novel protein overexpressed in various cancers, facilitates cell migration and invasion. In the present study we investigated the expression and role of MIEN1 in oral cancer progression using an in vitro model, patient derived oral tissues and existing TCGA data. Expression analysis using immortalized normal and cancer cells demonstrated increased expression of MIEN1 in cancer. Assays performed after MIEN1 knockdown in OSC-2 cells showed decreased migration, invasion and filopodia formation; while MIEN1 overexpression in DOK cells increased these characteristics and also up-regulated some Akt/NF-kB effectors, thereby suggesting an important role for MIEN1 in oral cancer progression. Immunohistochemical staining and analyses of oral tissue specimens, collected from patients over multiple visits, revealed significantly more staining in severe dysplasia and squamous cell carcinoma compared to mildly dysplastic or hyperplastic tissues. Finally, this was corroborated with the TCGA dataset, where MIEN1 expression was not only higher in intermediate and high grade cancer with significantly lower survival but also correlated with smoking. In summary, we demonstrate that MIEN1 expression not only positively correlates with oral cancer progression but also seems to be a critical molecular determinant in migration and invasion of oral cancer cells, thereby, playing a possible role in their metastatic dissemination.

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High expression levels of nuclear factor kappa B and gelatinases in the tumorigenesis of oral squamous cell carcinoma

Abstract: The results of this study suggest a regulatory role for NF-kappaB on activation of gelatinases during malignant transformation in the oral mucosa.

Cited by 65 publications

References 39 publications

Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-κB in Renal Cell Tumors

Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-κB in Renal Cell Tumors

Expression of NF‐κB parallels COX‐2 expression in oral precancer and cancer: Association with smokeless tobacco

MIEN1 promotes oral cancer progression and implicates poor overall survival

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