Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

Yang, Wei; Wang, Xiaoming; Yuan, Hongyan; Liu, Zhi‑Hui; Gao, Shuang; Peng, Liang

doi:10.3892/ol.2017.5850

Cited by 5 publications

(6 citation statements)

References 27 publications

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“…Further gene ontology on DEGs revealed that processes related to cancer hallmarks were frequently annotated; namely, cell cycle, proliferation, apoptosis, ECM organization, angiogenesis, EMT or migration. Many pathways appeared in at least three comparisons; MAPK, TGFβ, WNT, NOTCH or ERBB signaling were found to be dependent on WWOX, AP-2α and AP-2γ, i.e., MAPK [78][79][80], TGFβ [80][81][82], WNT [83,84], NOTCH [85][86][87] and ERBB [88,89]. Since WWOX is considered a global gene expression modulator [62] and both AP-2 transcription factors regulate thousands of genes and biological processes via specific pathways [79], it was foreseeable that changes in their expression affect cellular events at the broad scale.…”

Section: Discussionmentioning

confidence: 99%

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

Kołat

Kałuzińska

Płuciennik

2021

Cancers

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The cytogenic locus of the WWOX gene overlaps with the second most active fragile site, FRA16D, which is present at a higher frequency in bladder cancer (BLCA) patients with smoking habit, a known risk factor of this tumor. Recently, we demonstrated the relevance of the role of WWOX in grade 2 BLCA in collaboration with two AP-2 transcription factors whose molecular actions supported or opposed pro-cancerous events, suggesting a distinct character. As further research is needed on higher grades, the aim of the present study was to examine WWOX-AP-2 functionality in grade 3 and 4 BLCA using equivalent in vitro methodology with additional transcriptome profiling of cellular variants. WWOX and AP-2α demonstrated similar anti-cancer functionality in most biological processes with subtle differences in MMP-2/9 regulation; this contradicted that of AP-2γ, whose actions potentiated cancer progression. Simultaneous overexpression of WWOX and AP-2α/AP-2γ revealed that single discrepancies appear in WWOX-AP-2α collaboration but only at the highest BLCA grade; WWOX-AP-2α collaboration was considered anti-cancer. However, WWOX only appeared to have residual activity against oncogenic AP-2γ in grade 3 and 4: variants with either AP-2γ overexpression alone or combined WWOX and AP-2γ overexpression demonstrated similar pro-tumoral behavior. Transcriptome profiling with further gene ontology certified biological processes investigated in vitro and indicated groups of genes consisting of AP-2 targets and molecules worth investigation as biomarkers. In conclusion, tumor suppressor synergism between WWOX and AP-2α is unimpaired in high-grade BLCA compared to intermediate grade, yet the ability of WWOX to guide oncogenic AP-2γ is almost completely lost.

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Section: Discussionmentioning

confidence: 99%

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

Kołat

Kałuzińska

Płuciennik

2021

Cancers

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“…The identification of AP-2 targets and their functional annotation provided an insight into the signaling pathways in which they are involved. The data on the role of WWOX, AP-2α and AP-2γ in the regulation of MAPK [22][23][24], Wnt [25][26][27], Ras [28][29][30] and PI3K-…”

Section: Discussionmentioning

confidence: 99%

Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer

Kołat

Kałuzińska

Płuciennik

2022

Cells

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Following the invention of high-throughput sequencing, cancer research focused on investigating disease-related alterations, often inadvertently omitting tumor heterogeneity. This research was intended to limit the impact of heterogeneity on conclusions related to WWOX/AP-2α/AP-2γ in bladder cancer which differently influenced carcinogenesis. The study examined the signaling pathways regulated by WWOX-dependent AP-2 targets in cell lines as biological replicates using high-throughput sequencing. RT-112, HT-1376 and CAL-29 cell lines were subjected to two stable lentiviral transductions. Following CAGE-seq and differential expression analysis, the most important genes were identified and functionally annotated. Western blot was performed to validate the selected observations. The role of genes in biological processes was assessed and networks were visualized. Ultimately, principal component analysis was performed. The studied genes were found to be implicated in MAPK, Wnt, Ras, PI3K-Akt or Rap1 signaling. Data from pathways were collected, explaining the differences/similarities between phenotypes. FGFR3, STAT6, EFNA1, GSK3B, PIK3CB and SOS1 were successfully validated at the protein level. Afterwards, a definitive network was built using 173 genes. Principal component analysis revealed that the various expression of these genes explains the phenotypes. In conclusion, the current study certified that the signaling pathways regulated by WWOX and AP-2α have more in common than that regulated by AP-2γ. This is because WWOX acts as an EMT inhibitor, AP-2γ as an EMT enhancer while AP-2α as a MET inducer. Therefore, the relevance of AP-2γ in targeted therapy is now more evident. Some of the differently regulated genes can find application in bladder cancer treatment.

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“…As a precancerous lesion, OLK is involved in the process of carcinogenesis through 3 pathways of the KEGG pathway. Among 60 upregulated circRNA pathways, "proteoglycans in cancer," "miRNAs in cancer," and "pathways in cancer" are all involved in regulating the expression of extracellular-signal-regulated protein kinase/ mitogen-activated protein kinase (ERK/MAPK1), which have been proved to be crucial factors in the pathogenesis of OLK (31,32). This suggests that OLK is a risk of oral cancer on account of it being involved in several cancer-related pathways.…”

Section: Relative Expression Of Circerich1mentioning

confidence: 99%

Comprehensive analysis of circular RNA in oral leukoplakia: upregulated circHLA-C as a potential biomarker for diagnosis and prognosis

Xu¹,

Song²,

Shao³

et al. 2020

Ann Transl Med

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Background: Emerging evidence indicates that circular RNAs (circRNAs) play an indispensable role in a variety of tumors, yet the function of circRNAs in premalignant lesions is still obscure. Oral leukoplakia (OLK) is one of the most common premalignant lesions of the oral mucosa. Our study aimed to comprehensively investigate whether circRNAs contribute to the occurrence and development of OLK. Methods:We obtained six pairs of OLK and normal oral mucosal (NOM) tissue samples and subjected them to high-throughput sequencing to detect the expression of circRNA. In total, 26 pairs of NOM and OLK tissues were used for validation. Key circRNAs were selected and further validated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), ribonuclease (RNase) R digestion, and Sanger sequencing. Visualization analysis of circular human leukocyte antigen-C (circHLA-C) was performed in the UCSC Genome Browser (genome.ucsc.edu). Functional analysis of differentially expressed (DE) circRNAs were processed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Furthermore, TargetScan (www.targetscan.org) was applied to predict targeted micro RNAs (miRNAs) and messenger RNAs (mRNAs) of circRNAs and a competing endogenous RNA (ceRNA) network related with identified circRNAs was constructed in Cytoscape (v2.8.0).Results: Profile data showed that 366 circRNAs were significantly altered in OLK tissues, including 65 upregulated and 301 downregulated circRNA transcripts. Compared with sequencing results, seven selected circRNAs expressed the same changing tendency. The amplest upregulated circRNA in our sequencing data, circHLA-C, was confirmed through back-splice junction sequences by Sanger sequencing after RNase R digestion. Correlation analysis demonstrated that circHLA-C correlated positively with the degree of dysplasia. Furthermore, receiver operating characteristic (ROC) curve analysis indicated that circHLA-C had potential diagnostic value with excellent accuracy and specificity.Conclusions: According to the literature, we were the first to uncover the expression profiles of circRNAs in OLK. Our research performed a comprehensive bioinformatics analysis of DE circRNAs in OLK and identified circHLA-C as a promising diagnostic biomarker with potential as a therapeutic genetic target for OLK.

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Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

Cited by 5 publications

References 27 publications

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer

Comprehensive analysis of circular RNA in oral leukoplakia: upregulated circHLA-C as a potential biomarker for diagnosis and prognosis

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