Dataset Information

P-element Induced WImpy protein-like RNA-mediated gene silencing 2 regulates tumor cell progression, apoptosis, and metastasis in oral squamous cell carcinoma.

ABSTRACT:

Objective

P-element Induced WImpy protein-like RNA-mediated gene silencing 2 (PIWIL2) is a reported oncogene strongly associated with tumorigenesis and cancer progression. However, the potential function of PIWIL2 in oral cancer is still largely unclear.

Methods

In this study, we investigated the clinical significance of PIWIL2 expression in human oral squamous cell carcinoma (OSCC) cell lines and tissues. We also examined its function in OSCC pathogenesis by knocking down PIWIL2 expression with short hairpin RNAs, followed by phenotypic experiments focused on cell migration, invasion, proliferation, and apoptosis rates.

Results

We found that PIWIL2 was overexpressed in OSCC cell lines and tissues and significantly correlated with the malignancy stage. Furthermore, knockdown of PIWIL2 in a human OSCC cell line Tca8113 induced cell cycle arrest and apoptosis. Silencing PIWIL2 expression also significantly suppressed the migration and invasion abilities of Tca8113 cells.

Conclusions

Collectively, our results suggest a functional role of PIWIL2 in regulating OSCC pathogenesis. Our data imply that PIWIL2 could serve as a potential therapeutic target for OSCC treatment.

SUBMITTER: Zhou S

PROVIDER: S-EPMC8573518 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

P-element Induced WImpy protein-like RNA-mediated gene silencing 2 regulates tumor cell progression, apoptosis, and metastasis in oral squamous cell carcinoma.

Zhou Sen S Yang Song S Li Fang F Hou Jingying J Chang Hong H

The Journal of international medical research 20211101 11

<h4>Objective</h4>P-element Induced WImpy protein-like RNA-mediated gene silencing 2 (PIWIL2) is a reported oncogene strongly associated with tumorigenesis and cancer progression. However, the potential function of PIWIL2 in oral cancer is still largely unclear.<h4>Methods</h4>In this study, we investigated the clinical significance of PIWIL2 expression in human oral squamous cell carcinoma (OSCC) cell lines and tissues. We also examined its function in OSCC pathogenesis by knocking down PIWIL2 ...[more]

PMID: 34738477

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Project description:BackgroundEGFR is an important signal involved in tumor growth that can induce tumor metastasis and drug resistance. Exploring targets for effective EGFR regulation is an important topic in current research and drug development. Inhibiting EGFR can effectively inhibit the progression and lymph node metastasis of oral squamous cell carcinoma (OSCC) because OSCC is a type of cancer with high EGFR expression. However, the problem of EGFR drug resistance is particularly prominent, and identifying a new target for EGFR regulation could reveal an effective strategy.MethodsWe sequenced wild type or EGFR-resistant OSCC cells and samples from OSCC patients with or without lymph node metastasis to find new targets for EGFR regulation to effectively replace the strategy of directly inhibiting EGFR and exert an antitumor effect. We then investigated the effect of LCN2 on OSCC biological abilities in vitro and in vivo through protein expression regulation. Subsequently, we elucidated the regulatory mechanism of LCN2 through mass spectrometry, protein interaction, immunoblotting, and immunofluorescence analyses. As a proof of concept, a reduction-responsive nanoparticle (NP) platform was engineered for effective LCN2 siRNA (siLCN2) delivery, and a tongue orthotopic xenograft model as well as an EGFR-positive patient-derived xenograft (PDX) model were applied to investigate the curative effect of siLCN2.ResultsWe identified lipocalin-2 (LCN2), which is upregulated in OSCC metastasis and EGFR resistance. Inhibition of LCN2 expression can effectively inhibit the proliferation and metastasis of OSCC in vitro and in vivo by inhibiting EGFR phosphorylation and downstream signal activation. Mechanistically, LCN2 binds EGFR and enhances the recycling of EGFR, thereby activating the EGFR-MEK-ERK cascade. Inhibition of LCN2 effectively inhibited the activation of EGFR. We translated this finding by systemic delivery of siLCN2 by NPs, which effectively downregulated LCN2 in the tumor tissues, thereby leading to a significant inhibition of the growth and metastasis of xenografts.ConclusionsThis research indicated that targeting LCN2 could be a promising strategy for the treatment of OSCC.

Project description:BackgroundLate diagnosis is one of the major confounders in oral squamous cell carcinoma (OSCC). Despite recent advances in molecular diagnostics, no disease-specific biomarkers are clinically available for early risk prediction of OSCC. Therefore, it is important to identify robust biomarkers that are detectable using non-invasive liquid biopsy techniques to facilitate the early diagnosis of oral cancer. This study identified potential salivary exosome-derived miRNA biomarkers and crucial miRNA-mRNA networks/underlying mechanisms responsible for OSCC progression.MethodsSmall RNASeq (n = 23) was performed in order to identify potential miRNA biomarkers in both tissue and salivary exosomes derived from OSCC patients. Further, integrated analysis of The Cancer Genome Atlas (TCGA) datasets (n = 114), qPCR validation on larger patient cohorts (n = 70) and statistical analysis with various clinicopathological parameters was conducted to assess the effectiveness of the identified miRNA signature. miRNA-mRNA networks and pathway analysis was conducted by integrating the transcriptome sequencing and TCGA data. The OECM-1 cell line was transfected with the identified miRNA signature in order to observe its effect on various functional mechanisms such as cell proliferation, cell cycle, apoptosis, invasive as well as migratory potential and the downstream signaling pathways regulated by these miRNA-mRNA networks.ResultsSmall RNASeq and TCGA data identified 12 differentially expressed miRNAs in OSCC patients compared to controls. On validating these findings in a larger cohort of patients, miR-140-5p, miR-143-5p, and miR-145-5p were found to be significantly downregulated. This 3-miRNA signature demonstrated higher efficacy in predicting disease progression and clinically correlated with poor prognosis (p < 0.05). Transcriptome, TCGA, and miRNA-mRNA network analysis identified HIF1a, CDH1, CD44, EGFR, and CCND1 as hub genes regulated by the miRNA signature. Further, transfection-mediated upregulation of the 3-miRNA signature significantly decreased cell proliferation, induced apoptosis, resulted in G2/M phase cell cycle arrest and reduced the invasive and migratory potential by reversing the EMT process in the OECM-1 cell line.ConclusionsThus, this study identifies a 3-miRNA signature that can be utilized as a potential biomarker for predicting disease progression of OSCC and uncovers the underlying mechanisms responsible for converting a normal epithelial cell into a malignant phenotype.

Project description:Oral squamous cell carcinoma (OSCC) is the most frequent type of oral malignancy with high metastasis and poor prognosis. The deubiquitinating enzyme Ubiquitin Specific Peptidase 44 (USP44) regulates the mitotic checkpoint, and its deficiency leads to aneuploidy and increases tumor incidence. However, the role of USP44 in OSCC is not well understood. Herein, we analyzed mRNA sequencing data of OSCC samples downloaded from the TCGA and GEO databases and found that USP44 was decreased in human OSCC tissues and was positively correlated to the survival of OSCC patients. To investigate the biological impact of USP44, we used recombinant lentiviruses to overexpress or knockdown USP44 expression in OSCC cell lines, which were also injected subcutaneously or into the lateral tail vein of Male BALB/c nude mice to model tumorigenesis or lung metastasis in vivo, respectively. The results showed that overexpression of USP44 inhibited malignant cell phenotypes in vitro and suppressed tumor growth and lung metastasis in vivo, while its downregulation had the opposite effects. Comprehensive proteomic analyses through Co-IP mass spectrometry and label-free quantitative LC-MS/MS methods identified 112 differentially expressed proteins positively regulated by USP44, among which 13 were involved in cancer-related pathways including apoptotic signaling and cell cycle regulation. PPI analysis identified Hexamethylene Bis-Acetamide-Inducible Protein 1 (HEXIM1) as the hub protein. Upregulation of USP44 enhanced HEXIM1 protein stability, leading to its higher expression in OSCC cells. Silencing of HEXIM1 further enhanced the malignant phenotype of OSCC cells. At the same time, HEXIM1 knockdown reversed the antitumor effects of USP44. These findings demonstrated that USP44 acted as a critical tumor suppressor in OSCC by inhibiting cell proliferation and metastasis through the stabilization of HEXIM1 protein, suggesting that USP44-HEXIM1 axis is a promising target for OSCC therapy.

Dataset Information

P-element Induced WImpy protein-like RNA-mediated gene silencing 2 regulates tumor cell progression, apoptosis, and metastasis in oral squamous cell carcinoma.

Objective

Methods

Results

Conclusions

Publications

P-element Induced WImpy protein-like RNA-mediated gene silencing 2 regulates tumor cell progression, apoptosis, and metastasis in oral squamous cell carcinoma.

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