RIOK2 Contributes to Cell Growth and Protein Synthesis in Human Oral Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Matsuzaki Y
PROVIDER: S-EPMC9857684 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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RIOK2 Contributes to Cell Growth and Protein Synthesis in Human Oral Squamous Cell Carcinoma.
Matsuzaki Yusuke Y Naito Yutaka Y Miura Nami N Mori Taisuke T Watabe Yukio Y Yoshimoto Seiichi S Shibahara Takahiko T Takano Masayuki M Honda Kazufumi K
Current oncology (Toronto, Ont.) 20221226 1
Ribosomes are responsible for the protein synthesis that maintains cellular homeostasis and is required for the rapid cellular division of cancer cells. However, the role of ribosome biogenesis mediators in the malignant behavior of tongue squamous cell carcinoma (TSCC) is unknown. In this study, we found that the expression of RIOK2, a key enzyme involved in the maturation steps of the pre-40S ribosomal complex, was significantly associated with poorer overall survival in patients with TSCC. Fu ...[more]
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Project description:BACKGROUND:Inflammasomes are reported to be abnormally expressed and activated in several malignancies and play important roles in tumor development. The present study was designed to investigate the expression and function of the NLR family pyrin domain containing protein 3 (NLRP3) inflammasome in oral squamous cell carcinoma (OSCC). METHODS:NLRP3 expression in OSCC cell lines and the normal human immortalized oral epithelial cells (HIOEC) was determined by real-time PCR and western blot. Immunohistochemistry was used to examine the expression of NLRP3 and IL-1β in the paraffin-embedded OSCC tissues. The proliferation of OSCC cells was detected by the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and cell colony formation ability of the OSCC cells was also evaluated. Tumor cell migration or invasion was measured by the transwell assay and related protein markers were determined by western blot. A mouse xenograft model was established to investigate the OSCC tumor growth in vivo. RESULTS:Significant higher expression of NLRP3 was observed in the OSCC cells. Obvious expression of NLRP3 and IL-1β was found in the paraffin-embedded OSCC tissues, and the NLRP3 expression levels were correlated with the tumor size, lymphonode metastatic status and IL-1β expression. Downregulating NLRP3 expression markedly reduced the cleavage of caspase-1 and production of IL-1β in OSCC cells. NLRP3 knockdown also inhibited the proliferation, migration and invasion of OSCC cells. Further investigation indicated that expressions of E-cadherin and vimentin in OSCC cells were increased, while N-cadherin expression was decreased after NLRP3 knockdown. Downregulating NLRP3 expression in OSCC cells significantly reduced the tumor growth in vivo. CONCLUSIONS:Our data suggested that the increased expression of NLRP3 in OSCC was associated with tumor growth and metastasis. NLRP3 may be considered as a potential target for OSCC therapy.
| S-EPMC5930757 | biostudies-literature
Project description:ASC (Apoptosis-associated Speck-like protein containing a CARD) acts as a platform protein in the inflammasome cascade of some cancer types. However, its potential involvement in OSCC (oral cavity squamous cell carcinoma) has not yet been determined. Here, we investigated the potential role of ASC in OSCC. RT-qPCR analysis of 20 paired tumor and adjacent normal tissue samples revealed that the mRNA levels of ASC, along with IL-1β, CASP1, and NLRP3 in ASC-associated NLRP3 inflammasome were significantly elevated in OSCC tissues. Immunohistochemical staining of these four proteins in 111 clinical specimens revealed that high-level expression of ASC was significantly associated with tumor stage, node stage (p=0.001), overall stage (p<0.001), extracapsular spread (p<0.001), perineural invasion (p=0.004) and tumor depth (p<0.001). Kaplan-Meier survival analysis further revealed that high-level ASC expression was correlated with poorer overall survival (p=0.001), disease-specific survival (p<0.001) and disease-free survival (p<0.001). Studies using OSCC cell lines indicated that high-level ASC expression enhanced cell migration and invasion, and experiments using an orthotropic nude mouse model confirmed that ASC overexpression induced metastasis of OSCC cells. This is the first report to show that ASC contributes to OSCC metastasis, and that high-level ASC expression is a marker for poor prognosis in OSCC patients.
| S-EPMC5226569 | biostudies-literature
Project description:BackgroundThe therapeutic effectiveness of cisplatin, a widely used chemotherapy drug for oral squamous cell carcinoma (OSCC), is often compromised by resistance, making it difficult to predict treatment outcomes. The role of myotubularin and myotubularin-related (MTMR) genes in cisplatin resistance remains unclear. We aimed to elucidate the molecular mechanisms underlying MTMR6 with cisplatin resistance in OSCC.MethodsMTMR6 expression was compared between UMSCC1 and cisplatin-resistant UM-Cis cells. Gain- and loss-of-function experiments involving MTMR6 was performed to evaluate its impact on cisplatin resistance. The regulatory role of hsa-miR-544a on MTMR6 expression was explored via antagomir and miRNA mimic assays. The relationship between MTMR6 protein levels and cisplatin sensitivity was assessed in OSCC patient tissues classified as sensitive or resistant to cisplatin monotherapy. A survival analysis based on The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) dataset was performed to evaluate the correlation between MTMR6 expression and patient outcomes following cisplatin treatment. In vivo cisplatin resistance was examined using mouse xenografts derived from MTMR6-knockdown UMSCC1 cells.ResultsMTMR6 expression was markedly reduced in cisplatin-resistant UM-Cis cells compared to UMSCC1 cells. Functional analyses revealed that modulating MTMR6 activity alters cisplatin resistance. A luciferase assay confirmed that hsa-miR-544a regulates MTMR6 gene expression. Additionally, antagomir and miRNA mimics demonstrated that hsa-miR-544a enhances cisplatin resistance by suppressing MTMR6 expression. In OSCC patient tissues, higher MTMR6 protein levels were associated with cisplatin sensitivity, while cisplatin-resistant tissues had lower MTMR6 expression. Survival analysis of the TCGA HNSCC dataset indicated that low MTMR6 expression correlates with poorer outcomes in cisplatin-treated patients compared to those with high MTMR6 expression. Mouse xenografts derived from MTMR6-knockdown UMSCC1 cells exhibited increased resistance to cisplatin compared to controls.ConclusionAssessing mRNA levels of MTMR6 and has-miR-544a in biopsy samples could help predict cisplatin responsiveness in OSCC.
| S-EPMC11783708 | biostudies-literature
Project description:Aberrations of the fibroblast growth factor receptor 4 (FGFR4) genomic region include amplification of FGFR4, activation of FGFR4 kinase domain mutations, and overexpression of FGFR4, which lead to sustained cell proliferation and contribute to tumor development. However, the association between FGFR4 single-nucleotide polymorphisms (SNPs) and risk of oral squamous cell carcinoma (OSCC) remains to be determined. We investigated the relationships between FGFR4 genetic polymorphisms, OSCC development and clinicopathological variables. We recruited a total of 955 patients with OSCC and 1191 controls. Four SNPs of FGFR4 (rs2011077, rs351855, rs7708357, and rs1966265) were examined using real-time polymerase chain reaction. We found that with the rs351855 GA genotype and a combination of the GA and AA genotypes exhibited a 1.431-fold (95% CI: 1.092-1.876) and 1.335-fold (95% CI: 1.033-1.725) higher risk of OSCC. However, patients with OSCC with a homozygous A/A genotype of FGFR4 rs351855 polymorphism had a lower risk of advanced stage OSCC (P = 0.0252). Furthermore, the patients with the FGFR4 rs351855/rs1966265 A-A haplotype had a 2.890-fold (95% confidence interval [CI]: 2.257-3.700) higher risk of OSCC than the controls. Betel quid chewers with the A-A haplotype had a considerably higher risk (95% CI: 16.159-26.937) of OSCC than did betel quid nonchewers with other haplotypes. Moreover, an additional integrated in silico analysis proposed that rs351855 G allele variant to the A allele exhibited a relatively low energy of the transmembrane region. In conclusion, our results suggest that the FGFR4 rs351855 may play a role in susceptibility for OSCC development.
| S-EPMC5707095 | biostudies-literature
Project description:Oral squamous cell carcinoma (OSCC) is a cancer associated with high mortality (accounting for 3.1/100,000 deaths per year in Brazil in 2013) and a high frequency of amplification in the expression of the epidermal growth factor receptor (EGFR). Treatment with the EGFR inhibitor cetuximab leads to drug resistance in patients with OSCC due to unknown mechanisms. Galectin‑3 (Gal‑3) is a β‑galactoside binding lectin that regulates multiple signaling pathways in cells. The present study aimed to investigate the effect of Gal‑3 in cetuximab‑resistant (cet‑R) OSCC. The OSCC HSC3 cell line was selected to establish a mouse xenograft model, which was treated with cetuximab to induce resistance. Subsequently, a Gal‑3 inhibitor was used to treat cet‑R tumors, and the tumor volume was monitored. The expression of Gal‑3, phosphorylated (p)‑ERK1/2 and p‑Akt was assessed using immunohistochemistry. The combined effect of cetuximab and the Gal‑3 inhibitor on HSC3 tumor xenografts was also investigated. HSC3 cells were cultured in vitro to investigate the regulatory effects of Gal‑3 on ERK1/2 and Akt via western blotting. In addition, the effects of the Gal‑3 inhibitor on the proliferation, colony formation, invasion and apoptosis of HSC3 cells were investigated by performing Cell Counting Kit‑8, colony formation, Transwell and apoptosis assays, respectively. In cet‑R OSCC tumors, increased expression of Gal‑3, p‑ERK1/2 and p‑Akt was observed. Further research demonstrated that Gal‑3 regulated the expression of both ERK1/2 and Akt in HSC3 cells by promoting phosphorylation. Moreover, the Gal‑3 inhibitor decreased the proliferation and invasion, but increased the apoptosis of cet‑R HSC3 cells. In addition, the Gal‑3 inhibitor suppressed the growth of cet‑R tumors. Collectively, the results indicated that the Gal‑3 inhibitor and cetuximab displayed a synergistic inhibitory effect on OSCC tumors. In summary, the present study demonstrated that Gal‑3 may serve an important role in cet‑R OSCC. The combination of cetuximab and the Gal‑3 inhibitor may display a synergistic antitumor effect, thereby inhibiting the development of cetuximab resistance in OSCC.
| S-EPMC8365594 | biostudies-literature
Project description:Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor receptor tyrosine kinase family. It has been identified as a promising therapeutic target in multiple types of cancer. We have investigated FGFR3 protein expression and FGFR3 gene copy-numbers in a single well-documented cohort of oral and oropharyngeal squamous cell carcinoma. Tissue microarray sets containing 452 formalin-fixed paraffin-embedded tissues were immunohistochemically stained with an anti-FGFR3 antibody and hybridized with a FGFR3 fluorescence in situ hybridization probe. FGFR3 protein expression was correlated with clinicopathological and survival data, which were retrieved from electronic medical records. FGFR3 mRNA data of 522 head and neck squamous cell carcinoma (HNSCC) were retrieved from The Cancer Genome Atlas (TCGA). Fibroblast growth factor receptor 3 (FGFR3) protein was overexpressed in 48% (89/185) of oral and 59% (124/211) of oropharyngeal squamous cell carcinoma. Overexpression of FGFR3 protein was not related to overall survival or disease-free survival in oral (HR[hazard ratio]: 0.94; 95% CI: 0.64-1.39; P = 0.77, HR: 0.94; 95% CI: 0.65-1.36; P = 0.75) and oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81-1.80; P = 0.36, HR: 0.42; 95% CI: 0.79-1.77; P = 0.42). FGFR3 mRNA was upregulated in 3% (18/522) of HNSCC from the TCGA. The FGFR3 gene was gained in 0.6% (1/179) of oral squamous cell carcinoma but no amplification was found in oral and oropharyngeal squamous cell carcinoma. In conclusion, FGFR3 protein is frequently overexpressed in oral and oropharyngeal squamous cell carcinoma. Therefore, it may serve as a potential therapeutic target for FGFR3-directed therapies in oral and oropharyngeal squamous cell carcinoma.
| S-EPMC4735780 | biostudies-literature
Project description:Oral squamous cell carcinoma (OSCC) is a main reason of oral cancer mortality and morbidity. Cancer of oral cavity in central south Asia, ranks among third most common kinds of cancer. The discovery of candidate markers to differentiate normal from malignant cells in clinical diagnosis of OSCC would be of critical importance because this malignancy has poor prognosis. To improve the clinical outcome in OSCC patients, the present study was aimed at identifying robust candidate biomarkers for early OSCC diagnosis and to enhance understanding of the mechanisms of disease progression and pathogenesis. Of particular interest are proteins that can be found in tissue lysates of OSCC tumor vs normal adjacent mucosa samples and secreted in cell line Secretomes of HNSCC for non-invasive detection. We analysed 17 paired human malignant OSCC tissues and normal adjacent tissue in addition to secretomes of 9 HNSCC cell lines. The proteome dataset of OSCC and normal tissues consisted of 5,123 protein groups, including 299 proteins with strong differential expression (p-value <0.01, fold change barrier to ˃+2 and <-2, 205 upregulated and 94 down regulated) and 134 common proteins were also found out of total dataset of 4473 identified proteins of HNSCC cell line secretomes. Functional data analysis revealed that these differential proteins were significantly associated with multiple biological processes. Myogenesis, Fatty Acid Metabolism and KRAS Signaling DN were associated with the proteins downregulated in cancer tissues, while Protein Secretion, Unfolded Protein Response, Spliceosomal complex assembly, Protein localization to endosome and Interferon Gamma Response were enriched in the set of upregulated proteins and these regulated proteins may be classically or non-classically secreted. Furthermore, we found differential enrichment of Creb3L1, ESRRA, YY, ELF2, STAT1 and XBP transcription factors potentially regulating these major pathways.
2022-04-04 | PXD025701 | Pride
Project description:BackgroundOral squamous cell carcinoma (OSCC) is a main cause of oral cancer mortality and morbidity in central south Asia. To improve the clinical outcome of OSCC patients, detection markers are needed, which are preferably non-invasive and thus independent of a tissue biopsy.MethodsIn the present study, we aimed to identify robust candidate protein biomarkers for non-invasive OSCC diagnosis. To this end, we measured the global protein profiles of OSCC tissue lysates to matched normal adjacent mucosa samples (n = 14) and the secretomes of nine HNSCC cell lines using LC-MS/MS-based proteomics.ResultsA total of 5123 tissue proteins were identified, of which 205 were robustly up- regulated (p-value < 0.01, fold change > + 2) in OSCC-tissues compared to normal adjacent tissues. The biological process "Secretion" was highly enriched in this set of proteins. Other upregulated biological pathways included "Unfolded Protein Response", "Spliceosomal complex assembly", "Protein localization to endosome" and "Interferon Gamma Response". Transcription factor analysis implicated Creb3L1, ESRRA, YY, ELF2, STAT1 and XBP as potential regulators. Of the 205 upregulated tissue proteins, 132 were identified in the cancer cell line secretomes, underscoring their potential use as non-invasive biofluid markers. To further prioritize our candidate markers for non-invasive OSCC detection, we integrated our data with public biofluid datasets including OSCC saliva, yielding 25 candidate markers for further study.ConclusionsWe identified several key proteins and processes that are associated with OSCC tissues, underscoring the importance of altered secretion. Cancer-associated OSCC secretome proteins present in saliva have potential to be used as novel non-invasive biomarkers for the diagnosis of OSCC.
| S-EPMC8903575 | biostudies-literature
Project description:WNT1-inducible-signaling pathway protein-1 (WISP-1) belongs to the family of cysteine rich 61/connective tissue growth factor/nephroblastoma overexpressed matricellular proteins, which are involved in various biological processes, including cell adhesion, proliferation, differentiation, angiogenesis and carcinogenesis. In the present study, the expression of WISP-1 was investigated, and its association with clinicopathological factors and prognosis in patients with oral squamous cell carcinoma (OSCC) was evaluated. Additionally, the role of WISP-1 in invasion and apoptosis of human OSCC cells was evaluated. Immunoreactivity of WISP-1 was increased in OSCC tissue compared with adjacent normal tissue samples. High expression of WISP-1 protein was observed in 24/84 (28.57%) OSCC specimens. Additionally, high WISP-1 expression was significantly associated with treatment failure (P=0.042). The 5-year overall survival rate was 33% in patients with high WISP1 expression, and 66% in patients with low WISP-1 expression. WISP-1 expression in the human OSCC SCC-1483 cell line was observed. Furthermore, WISP-1 knockdown using small interfering (si)RNA significantly reduced cell invasion and induced apoptosis compared with control siRNA-transfected cells. These findings suggested that WISP-1 is associated with tumor progression and poor prognosis by increasing tumor cell invasion and inhibiting cell apoptosis in human OSCC.
| S-EPMC5529834 | biostudies-other
Project description:Hepatocyte growth factor activator inhibitor (HAI)-1/SPINT1 and HAI-2/SPINT2 are membrane-anchored protease inhibitors having homologous Kunitz-type inhibitor domains. They regulate membrane-anchored serine proteases, such as matriptase and prostasin. Whereas HAI-1 suppresses the neoplastic progression of keratinocytes to invasive squamous cell carcinoma (SCC) through matriptase inhibition, the role of HAI-2 in keratinocytes is poorly understood. In vitro homozygous knockout of the SPINT2 gene suppressed the proliferation of two oral SCC (OSCC) lines (SAS and HSC3) but not the growth of a non-tumorigenic keratinocyte line (HaCaT). Reversion of HAI-2 abrogated the growth suppression. Matrigel invasion of both OSCC lines was also suppressed by the loss of HAI-2. The levels of prostasin protein were markedly increased in HAI-2-deficient cells, and knockdown of prostasin alleviated the HAI-2 loss-induced suppression of OSCC cell invasion. Therefore, HAI-2 has a pro-invasive role in OSCC cells through suppression of prostasin. In surgically resected OSCC tissues, HAI-2 immunoreactivity increased along with neoplastic progression, showing intense immunoreactivities in invasive OSCC cells. In summary, HAI-2 is required for invasive growth of OSCC cells and may contribute to OSCC progression.
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