Characterization of Recurrent Relevant Genes Reveals a Novel Role of RPL36A in Radioresistant Oral Squamous Cell Carcinoma

Abstract

Radioresistance is one of the major factors that contributes to radiotherapy failure in oral cavity squamous cell carcinoma (OSCC). By comparing the prognostic values of 20,502 genes expressed in patients in The Cancer Genome Atlas (TCGA)-OSCC cohort with (n = 162) and without radiotherapy (n = 118), herein identified 297 genes positively correlated with poor disease-free survival in OSCC patients with radiotherapy as the potential radioresistance-associated genes. Among the potential radioresistance-associated genes, 36 genes were upregulated in cancerous tissues relative to normal tissues. The bioinformatics analysis revealed that 60S ribosomal protein L36a (RPL36A) was the most frequently detected gene involved in radioresistance-associated gene-mediated biological pathways. Then, two independent cohorts (n = 162 and n = 136) were assessed to confirm that higher RPL36A transcript levels were significantly associated with a poor prognosis only in OSCC patients with radiotherapy. Mechanistically, we found that knockdown of RPL36A increased radiosensitivity via sensitizing cells to DNA damage and promoted G2/M cell cycle arrest followed by augmenting the irradiation-induced apoptosis pathway in OSCC cells. Taken together, our study supports the use of large-scale genomic data for identifying specific radioresistance-associated genes and suggests a regulatory role for RPL36A in the development of radioresistance in OSCC.

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

“…For example, nuclear factor erythroid 2-related factor 2 (Nrf2) was recently shown to be upregulated in clinically relevant radioresistant OSCC cells, and to be involved in the development of IR resistance via enhancing Nrf2-dependent glycolysis and glutathione synthesis [34]. Chen et al found that 60S ribosomal protein L36a (RPL36A) was closely related to poor prognosis in patients with OSCC treated with radiotherapy, and depletion of RPL36A sensitized OSCC cells to DNA damage and promoted G 2 /M cell cycle arrest to upregulate IR-induced apoptosis, which led to increased radiosensitivity in OSCC cells [23]. MicroRNA-125b was reported to be downregulated in OSCC cells, and exhibited an antitumor effect by reducing cell proliferation and enhancing radiosensitivity through the regulation of intercellular adhesion molecule-2 signaling [36].…”

“…As previously reported, resistance to radiotherapy is a primary factor for treatment failure in OSCC [23]. To better understand this observation, radioresistant OSCC cell lines CAL27R and SCC25R were established using the parental CAL27 and SCC25 cells, respectively.…”

Mitochondrial Ribosomal Protein MRPS15 Is a Component of Cytosolic Ribosomes and Regulates Translation in Stressed Cardiomyocytes

“…A study reported that the transcription of RPS27A/eS31 mRNA is increased in a p53-dependent manner, while a recent report showed that DNA double-strand breaks trigger the loss of this protein from ribosomes [ 47 , 48 ]. RPL36A/eL42 is upregulated in radioresistant tumors, while RPL37/eL37 expression increases in hypoxia and acidosis conditions [ 49 ]. All these observations suggest that the expression of RPs identified in our study is regulated and that they can contribute to ribosome heterogeneity, although we cannot rule out the possibility of an extraribosomal role.…”

Mitochondrial Ribosomal Protein L14 Promotes Cell Growth and Invasion by Modulating Reactive Oxygen Species in Thyroid Cancer

“…For instance, the knockdown of ribosomal protein S27a (RPS27A) improved the therapeutic efficacy of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia [30]. Silencing of ribosomal protein large P (RPLP) promoted apoptosis and decreased radio-resistance in vitro in head and neck squamous cell cancer [31]. Furthermore, MRPL33 enhanced the sensitivity of gastric cancer cells to epirubicin, a chemotherapy drug [32].…”