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Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma.

ABSTRACT: To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6, IL1B and ISG15) and six genes from the RNA-seq and proteomics crossover (AKR1C3, TNFAIP2, RAB7A, LGALS3BP, PSCA and SSRP1) were selected to be studied by qRT-PCR in 11 HNSCC patients: six resistant and five sensitive to conventional therapy. Interestingly, the high MAGEB2 expression was associated with resistant tumours and is revealed as a novel target to sensitise resistant cells to therapy in HNSCC patients.

SUBMITTER: Garcia-Mayea Y

PROVIDER: S-EPMC9688094 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma.

Garcia-Mayea Yoelsis Y Benítez-Álvarez Lisandra L Sánchez-García Almudena A Bataller Marina M Companioni Osmel O Mir Cristina C Benavente Sergi S Lorente Juan J Canela Nuria N Fernández-Rozadilla Ceres C Carracedo Angel A LLeonart Matilde E ME

Cancers 20221109 22

To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 do ...[more]

PMID: 36428603

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Project description:BackgroundDrug resistance limits the treatment effect of cisplatin-based chemotherapy in head and neck squamous cell carcinoma (HNSCC), and the underlying mechanism is not fully understood. The aim of this study was to explore the cause of cisplatin resistance in HNSCC.MethodsWe performed survival and gene set variation analyses based on HNSCC cohorts and identified the critical role of tumor necrosis factor alpha-induced protein 2 (TNFAIP2) in cisplatin-based chemotherapy resistance. Half-maximal inhibitory concentration (IC50) examination, colony formation assays and flow cytometry assays were conducted to examine the role of TNFAIP2 in vitro, while xenograft models in nude mice and 4-nitroquinoline N-oxide (4NQO)-induced HNSCC models in C57BL/6 mice were adopted to verify the effect of TNFAIP2 in vivo. Gene set enrichment analysis (GSEA) and coimmunoprecipitation coupled with mass spectrometry (Co-IP/MS) were performed to determine the mechanism by which TNFAIP2 promotes cisplatin resistance.ResultsHigh expression of TNFAIP2 is associated with a poor prognosis, cisplatin resistance, and low reactive oxygen species (ROS) levels in HNSCC. Specifically, it protects cancer cells from cisplatin-induced apoptosis by inhibiting ROS-mediated c-JUN N-terminal kinase (JNK) phosphorylation. Mechanistically, the DLG motif contained in TNFAIP2 competes with nuclear factor-erythroid 2-related factor 2 (NRF2) by directly binding to the Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), which prevents NRF2 from undergoing ubiquitin proteasome-mediated degradation. This results in the accumulation of NRF2 and confers cisplatin resistance. Positive correlations between TNFAIP2 protein levels and NRF2 as well as its downstream target genes were validated in HNSCC specimens. Moreover, the small interfering RNA (siRNA) targeting TNFAIP2 significantly enhanced the cisplatin treatment effect in a 4NQO-induced HNSCC mouse model.ConclusionsOur results reveal the antioxidant and cisplatin resistance-regulating roles of the TNFAIP2/KEAP1/NRF2/JNK axis in HNSCC, suggesting that TNFAIP2 might be a potential target in improving the cisplatin treatment effect, particularly for patients with cisplatin resistance.

Project description:BackgroundNormal epithelial cells rapidly undergo apoptosis as soon as they lose contact with the extracellular matrix (ECM), which is termed as anoikis. However, cancer cells tend to develop a resistance mechanism to anoikis. This acquired ability is termed as anoikis resistance. Cancer cells, with anoikis resistance, can spread to distant tissues or organs via the peripheral circulatory system and cause cancer metastasis. Thus, inhibition of anoikis resistance blocks the metastatic ability of cancer cells.MethodsAnoikis-resistant CAL27 (CAL27AR) cells were induced from CAL27 cells using the suspension culture approach. Transcriptome analysis was performed using RNA-Seq to study the differentially expressed genes (DEGs) between the CAL27ARcells and the parental CAL27 cells. Gene function annotation and Gene Ontology (GO) enrichment analysis were performed using DAVID database. Signaling pathways involved in DEGs were analyzed using Gene Set Enrichment Analysis (GSEA) software. Analysis results were confirmed by reverse transcription PCR (RT-PCR), western blotting, and gene correlation analysis based on the TCGA database.ResultsGO enrichment analysis indicated that the biological process (BP) of the DEGs was associated with epidermal development, DNA replication, and G1/S transition of the mitotic cell cycle. The analysis of cellular component (CC) showed that the most significant up-regulated genes were related to extracellular exosome. KEGG Pathway analysis revealed that 23 signaling pathways were activated (p-value ≤ 0.05, FDR q-value ≤ 0.05) and 22 signaling pathways were suppressed (p-value ≤ 0.05, FDR q-value ≤ 0.05). The results from the GSEA indicated that in contrast to the inhibition of EGFR signaling pathway, the VEGF signaling pathway was activated. The VEGF signaling pathway possibly activates STAT3 though induction of STAT3 phosphorylation. Gene correlation analysis revealed that the VEGFA- STAT3-KLF4-CDKN1A signal axis was not only present in head and neck squamous carcinoma (HNSCC) but also two other epithelial-derived carcinomas that highly express VEGFA, including kidney renal clear cell carcinoma (KIRC) and ovarian serous cystadenocarcinoma (OV).

Dataset Information

Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma.

Publications

Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma.

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