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Ubiquitin D Promotes Progression of Oral Squamous Cell Carcinoma via NF-Kappa B Signaling.

ABSTRACT: Ubiquitin D (UBD) is highly upregulated in many cancers, and plays a pivotal role in the pathophysiological processes of cancers. However, its roles and underlying mechanisms in oral squamous cell carcinoma (OSCC) are still unclear. In the present study, we investigated the role of UBD in patients with OSCC. Quantitative real-time polymerase chain reaction and Western blot were used to measure the expression of UBD in OSCC tissues. Immunohistochemistry assay was used to detect the differential expressions of UBD in 244 OSCC patients and 32 cases of normal oral mucosae. In addition, CCK-8, colony formation, wound healing and Transwell assays were performed to evaluate the effect of UBD on the cell proliferation, migration, and invasion in OSCC. Furthermore, a xenograft tumor model was established to verify the role of UBD on tumor formation in vivo. We found that UBD was upregulated in human OSCC tissues and cell lines and was associated with clinical and pathological features of patients. Moreover, the overexpression of UBD promoted the proliferation, migration and invasion of OSCC cells; however, the knockdown of UBD exerted the opposite effects. In this study, our results also suggested that UBD promoted OSCC progression through NF-κB signaling. Our findings indicated that UBD played a critical role in OSCC and may serve as a prognostic biomarker and potential therapeutic target for OSCC treatment.

SUBMITTER: Song A

PROVIDER: S-EPMC8334351 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Ubiquitin D Promotes Progression of Oral Squamous Cell Carcinoma via NF-Kappa B Signaling.

Song An A Wang Yi Y Jiang Feng F Yan Enshi E Zhou Junbo J Ye Jinhai J Zhang Hongchuang H Ding Xu X Li Gang G Wu Yunong Y Zheng Yang Y Song Xiaomeng X

Molecules and cells 20210701 7

Ubiquitin D (UBD) is highly upregulated in many cancers, and plays a pivotal role in the pathophysiological processes of cancers. However, its roles and underlying mechanisms in oral squamous cell carcinoma (OSCC) are still unclear. In the present study, we investigated the role of UBD in patients with OSCC. Quantitative real-time polymerase chain reaction and Western blot were used to measure the expression of UBD in OSCC tissues. Immunohistochemistry assay was used to detect the differential e ...[more]

PMID: 34230226

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Project description:BackgroundTumor dissemination is a life-threatening event which confers to most cancer-related deaths with limited effective therapeutic option. TNFα-induced protein 2 (TNFAIP2) reveals pro-metastasis potential in several cancers. However, its definite role and underlying mechanism in oral squamous cell carcinoma (OSCC) is largely unknown.MethodsThe impact of TNFAIP2 on tumor metastasis was assessed based on the conditional knockout mouse with 4-nitroquinoline-1-oxide (4NQO) induced OSCC model through feature and immunohistochemistry analysis. To explore the specific mechanism, enrichment analysis and co-immunoprecipitation were applied. Meanwhile, the nano-hydroxyapatite (nHAp) and poly-L-lysine (PLL) based RNA interference delivery system was designed to restrict tumor dissemination.ResultsThe conditional knockout Tnfaip2 in epithelium reduced tumor initiation rate, differentiation degree and cervical lymph node metastasis (LNM) in mouse exposed to 4NQO. Enrichment analysis suggested nuclear factor-kappa B (NF-κB) signaling was associated with these effects. Western blot proved that TNFAIP2 prevented the ubiquitin proteasome degradation of inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKβ), a classical transcriptional activator protein in NF-κB signaling. Mechanistically, TNFAIP2 was demonstrated to competitively interact with kelch-like ECH-associated protein 1 (KEAP1) to avoid IKKβ from ubiquitination at K63 and proteasomal degradation subsequently, which finally sustained NF-κB signaling and facilitated tumor metastasis by enhancing epithelial-mesenchymal transition (EMT) and lymphangiogenesis. Notably, the synthetic small interfering RNA delivery systems nHAp@PLL-siTnfaip2 showed significant effect in attenuating tumor progression of OSCC mouse.ConclusionAbove results showed TNFAIP2 promoted EMT and lymphangiogenesis of OSCC by regulating NF-κB signaling, a mechanism that was dependent on the interaction with KEAP1 competitively. The nHAp based TNFAIP2 interference might serve as a novel therapeutic in limiting OSCC metastasis.

Project description:Tumor dissemination is a life-threatening event which confers to most cancer-related deaths with limited effective therapeutic option. TNFα-induced protein 2 (TNFAIP2) reveals pro-metastasis potential in several cancers. However, its definite role and underlying mechanism in oral squamous cell carcinoma (OSCC) is largely unknown. The impact of TNFAIP2 on tumor metastasis was assessed based on the conditional knockout mouse with 4-nitroquinoline-1-oxide (4NQO) induced OSCC through feature and immunohistochemistry analysis. To explore the specific mechanism and intervention means, enrichment analysis and co-immunoprecipitation were also applied, together with designing the nano-hydroxyapatite (nHAp) based RNA interference delivery system to restrict tumor dissemination. The epithelium conditional knockout Tnfaip2 reduced tumor initiation rate, differentiation degree and cervical lymph node metastasis (LNM) in mouse exposed to 4NQO. Enrichment analysis suggested NF-κB signaling was associated with these effects. Western blot proved that TNFAIP2 prevented the ubiquitin proteasome degradation of inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKβ), a classical transcriptional activator protein in NF-κB signaling. Mechanistically, it was demonstrated that TNFAIP2 completely interacted with kelch-like ECH-associated protein 1 (KEAP1) to avoid IKKβ from ubiquitination at K63 and subsequent proteasomal degradation, which finally sustained NF-κB signaling and facilitated tumor metastasis by enhancing epithelial-mesenchymal transition (EMT) and lymphangiogenesis. Notably, the synthetic small interfering RNA delivery systems nHAp@PLL-siTnfaip2 showed significant effect in attenuating tumor progression of OSCC mouse. Above results showed TNFAIP2 promoted the EMT and lymphangiogenesis of OSCC by regulating NF-κB signaling, a mechanism that was dependent on the interaction with KEAP1 completely. The nHAp based TNFAIP2 interference might serve as novel therapeutics in limiting OSCC metastasis.

Project description:BackgroundFascin is a globular actin cross-linking protein, which plays a major role in forming parallel actin bundles in cell protrusions and is found to be associated with tumor cell invasion and metastasis in various type of cancers including oral squamous cell carcinoma (OSCC). Previously, we have demonstrated that fascin regulates actin polymerization and thereby promotes cell motility in K8-depleted OSCC cells. In the present study we have investigated the role of fascin in tumor progression of OSCC.MethodsTo understand the role of fascin in OSCC development and/or progression, fascin was overexpressed along with vector control in OSCC derived cells AW13516. The phenotype was studied using wound healing, Boyden chamber, cell adhesion, Hanging drop, soft agar and tumorigenicity assays. Further, fascin expression was examined in human OSCC samples (N = 131) using immunohistochemistry and level of its expression was correlated with clinico-pathological parameters of the patients.ResultsFascin overexpression in OSCC derived cells led to significant increase in cell migration, cell invasion and MMP-2 activity. In addition these cells demonstrated increased levels of phosphorylated AKT, ERK1/2 and JNK1/2. Our in vitro results were consistent with correlative studies of fascin expression with the clinico-pathological parameters of the OSCC patients. Fascin expression in OSCC showed statistically significant correlation with increased tumor stage (P = 0.041), increased lymph node metastasis (P = 0.001), less differentiation (P = 0.005), increased recurrence (P = 0.038) and shorter survival (P = 0.004) of the patients.ConclusionIn conclusion, our results indicate that fascin promotes tumor progression and activates AKT and MAPK pathways in OSCC-derived cells. Further, our correlative studies of fascin expression in OSCC with clinico-pathological parameters of the patients indicate that fascin may prove to be useful in prognostication and treatment of OSCC.

Dataset Information

Ubiquitin D Promotes Progression of Oral Squamous Cell Carcinoma via NF-Kappa B Signaling.

Publications

Ubiquitin D Promotes Progression of Oral Squamous Cell Carcinoma via NF-Kappa B Signaling.

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