Dataset Information

HOTTIP Functions as a Key Candidate Biomarker in Head and Neck Squamous Cell Carcinoma by Integrated Bioinformatic Analysis.

ABSTRACT: Background:Accumulating evidence has demonstrated the pivotal role of long noncoding RNAs (lncRNAs) in competing endogenous RNA (ceRNA) networks for predicting survival and evaluating prognosis in cancer patients. However, the pathogenesis of head and neck squamous cell carcinoma (HNSCC) remains unclear, and prognostic biomarkers for HNSCC are still lacking. Methods:A total of 546 RNA sequencing profiles of HNSCC patients with clinical outcome data were obtained from the Cancer Genome Atlas (TCGA) database, providing a large sample of RNA sequencing data. From these, 71 Long noncoding RNAs lncRNAs, 8 microRNAs (miRNAs), and 16 messenger RNAs (mRNAs) were identified to construct a HNSCC-specific ceRNA network (fold change >2, P < 0.05). Univariate and multivariate Cox proportional regression models were used to assess independent indicators of prognosis. Then the expression of lncRNAs harboring prognostic value was validated in human HNSCC cell lines and tumor samples from our cohort and another two datasets from GEO (Gene Expression Omnibus) databases. Results:As a result, a 3-mRNA signature and 6-lncRNA signature were identified. The six-lncRNA signature exhibited the highest prognostic value. Notably, in the six lncRNAs, HOTTIP showed the greatest prognostic value and was significantly correlated with clinical stage and histological grade of HNSCC patients. Furthermore, it was proved that HOTTIP was upregulated in HNSCC cell lines and cancerous tissues compared with corresponding normal cell lines and normal tissues. Functional assessment analysis revealed that HOTTIP might play a key role in the oncogenesis and progression of HNSCC. Conclusion:The present study deepened our understanding of the ceRNA-related regulatory mechanism in the pathogenesis of HNSCC and identified candidate prognostic biomarkers for clinical outcome prediction in HNSCC. HOTTIP may function as a key candidate biomarker in HNSCC and serve as a prognostic marker for HNSCC patients.

SUBMITTER: Yin X

PROVIDER: S-EPMC6457310 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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HOTTIP Functions as a Key Candidate Biomarker in Head and Neck Squamous Cell Carcinoma by Integrated Bioinformatic Analysis.

Yin Xiteng X Yang Weidong W Xie Junqi J Wei Zheng Z Tang Chuanchao C Song Chuanhui C Wang Yufeng Y Cai Yu Y Xu Wenguang W Han Wei W

BioMed research international 20190326

<h4>Background</h4>Accumulating evidence has demonstrated the pivotal role of long noncoding RNAs (lncRNAs) in competing endogenous RNA (ceRNA) networks for predicting survival and evaluating prognosis in cancer patients. However, the pathogenesis of head and neck squamous cell carcinoma (HNSCC) remains unclear, and prognostic biomarkers for HNSCC are still lacking.<h4>Methods</h4>A total of 546 RNA sequencing profiles of HNSCC patients with clinical outcome data were obtained from the Cancer Ge ...[more]

PMID: 31032351

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Project description:Exosomes serve as a crucial mode of communication between tumor-associated macrophages (TAMs) and cancer cells. This study attempted to explore the function of M1-derived exosomes and clarify their specific mechanism in head and neck squamous cell carcinoma (HNSCC). Moreover, the functional roles of M1-derived exosomes and their key molecule long noncoding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) in HNSCC were investigated by conducting a series of in vitro and in vivo experiments. The dual-luciferase test was utilized to clarify the binding capacities between HOTTIP/mRNA and miRNAs. Accordingly, HOTTIP was found to be upregulated in M1-derived exosomes. Meanwhile, the in vitro experiments indicated that M1 exosomes suppressed proliferation, migration and invasion but induced apoptosis of cancer cells. This function was noted to be enhanced by HOTTIP-overexpressed M1 exosomes but was weakened by HOTTIP-knockdown ones, indicating that HOTTIP serves as a key molecule in M1 exosomes. Therefore, the function of HOTTIP in cancer cells was explored, for which overexpression of HOTTIP was found to inhibit proliferation, migration and invasion but induced apoptosis of cancer cells in vitro. A mechanism study further showed that M1 exosomes and HOTTIP activated the TLR5/NF-κB signaling pathway by competitively sponging miR-19a-3p and miR-19b-3p. Furthermore, cancer cells expressing HOTTIP were noted to induce the polarization of both local M1 and M2 macrophages; however, M1 exosomes were observed to reprogram local TAMs into M1 macrophages. More importantly, both cancer cells expressing HOTTIP and M1 exosomes reeducated circulating monocytes to express the M1 phenotype. The corresponding data demonstrated that the M1 exosomal lncRNA HOTTIP suppresses HNSCC progression by upregulating the TLR5/NF-κB signaling pathway through competitively sponging miR-19a-3p and miR-19b-3p. In particular, M1 exosomes and HOTTIP induce the polarization of M1 in circulating monocytes, thus providing novel insight into HNSCC immunotherapy.

Project description:Head and neck squamous cell carcinomas (HNSCC) can arise from the oral cavity, oropharynx, larynx or hypopharynx, and is the sixth leading cancer by incidence worldwide. The 5-year survival rate of HNSCC patients remains static at 40-60%. Hence, biomarkers which can improve detection of HNSCC or early recurrences should improve clinical outcome. Mass spectrometry-based proteomics methods have emerged as promising approaches for biomarker discovery. As one approach, mass-spectrometric identification of proteins shed or secreted from cancer cells can contribute to the identification of potential biomarkers for HNSCC and our understanding of tumor behavior. In the current study, mass spectrometry-based proteomic profiling was performed on the conditioned media (i.e. secretome) of head and neck cancer (HNC) cell lines (FaDu, UTSCC8 and UTSCC42a) in addition to gene expression microarrays to identify over-expressed transcripts in the HNSCC cells in comparison to a normal control cell line. This integrated data set was systematically mined using publicly available resources (Human Protein Atlas and published proteomic/transcriptomic data) to prioritize putative candidates for validation. Subsequently, quantitative real-time PCR (qRT-PCR), Western blotting, immunohistochemistry (IHC), and ELISAs were performed to verify selected markers. Our integrated analyses identified 90 putative protein biomarkers that were secreted or shed to the extracellular space and over-expressed in HNSCC cell lines, relative to controls. Subsequently, the over-expression of five markers was verified in vitro at the transcriptional and translational levels using qRT-PCR and Western blotting, respectively. IHC-based validation conducted in two independent cohorts comprising of 40 and 39 HNSCC biopsies revealed that high tumor expression of PLAU, IGFBP7, MMP14 and THBS1 were associated with inferior disease-free survival, and increased risk of disease progression or relapse. Furthermore, as demonstrated using ELISAs, circulating levels of PLAU and IGFBP7 were significantly higher in the plasma of HNSCC patients compared with healthy individuals.

Dataset Information

HOTTIP Functions as a Key Candidate Biomarker in Head and Neck Squamous Cell Carcinoma by Integrated Bioinformatic Analysis.

Publications

HOTTIP Functions as a Key Candidate Biomarker in Head and Neck Squamous Cell Carcinoma by Integrated Bioinformatic Analysis.

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