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MALAT1 Decreases the Sensitivity of Head and Neck Carcinoma Cells Radiation and Cisplatin

Background/Aim: Two-thirds of head and neck squamous cell carcinoma (HNSCC) patients present with locally advanced (LA) stages and have a poor survival rate. The aim of this study was to investigate the roles of the long non-coding RNAs MALAT1 on radiation and cisplatin sensitivity of HNSCC cells. Materials and Methods: Clonogenic, cell viability, and apoptosis assays were performed in cells following MALAT1 knockdown using CRISPR/Cas9 system.

Results: MALAT1 was overexpressed in HNSCC cell lines as compared to a non-tumorigenic cell line. The number of colonies formed after radiation was significantly reduced in MALAT1 knockdown cells. The IC50 value of cisplatin in MALAT1 knockdown cells was lower than that of the control cells. MALAT1 knockdown resulted in cell cycle arrest at G2/M phase, DNA damage and apoptotic cell death.

Conclusion: MALAT1 knockdown enhanced the sensitivity of HNSCC cells to radiation and cisplatin partly through the induction of G2/M cell cycle arrest resulting in DNA damage and apoptosis

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors arising from epithelial cells of the oral cavity, nasal cavity, pharynx, larynx, and hypopharynx. HNSCC is the sixth most common cancer worldwide in which two-third of patients are diagnosed with locally advanced stage. Annually, approximately 700,000 new HNSCC cases and 350,000 death are reported . Concurrent chemoradiotherapy (CRT) using platinum-based chemotherapy (e.g. cisplatin or carboplatin) and/or surgery are considered a standard treatment for locally advanced (LA) HNSCC patients. Cisplatin is considered as the mainstay chemotherapy agent for CRT in patients with LAHNSCC. Nevertheless, the majority of LA-HNSCC patients suffer from locoregional recurrence due to CRT resistance, and the overall survival (OS) rate remains poor . Therefore, understanding the mechanism of radiotherapy and cisplatin sensitivity in HNSCC is essential to improve survival outcome of LA-HNSCC patients. Long non-coding RNAs (lncRNAs) are a novel class of non-protein coding transcripts containing >200 nucleotides . Increasing evidence has reported the critical roles of lncRNAs in the regulation of multiple cellular processes (5). The molecular mechanism relies on the interaction of lncRNAs with other biomolecules including chromatin, protein and RNA (6). They also play a role in epigenetic regulation through the recruitment of chromatin-modifying complexes to specific genomic DNA targets (7). Moreover, lncRNA can also function as endogenous sponge for other RNAs, such as mRNAs and miRNAs to regulate their stability and translation (8). Alteration of lncRNA functions has been shown to associate with treatment sensitivity of cancer cells through multiple cellular processes, such as chromatin modification, DNA damage and repair mechanism, cell cycle control, and mRNA processing and stability . Recently, the differential expression of lncRNA between HNSCC and their adjacent normal tissues has been revealed. The study reported that down-regulation of two lncRNAs, lnc-LCE5A-1 and lnc-KCTD6-3, was significantly associated with poor prognosis of HNSCC patients. In addition to the aforementioned lncRNAs, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) also plays critical roles in cancer carcinogenesis and progression. MALAT1 has been shown to be dramatically upregulated in various types of cancer including HNSCC . Up-regulation of MALAT1 was associated with poor prognosis and promoted cell proliferation and migration of TSCC (tongue squamous cell carcinoma) and LSCC (laryngeal squamous cell carcinoma) . Down-regulation of MALAT1 in HR-HPV+ cervical cancer increased its sensitivity to radiation via sponging of miR-145 . However, a role of MALAT1 in regulating radiation and cisplatin sensitivity of HNSCC cells, which is a key treatment of LA-HNSCC patients, has not been explored.1

s. (C) MALAT1 stable knockdown FaDu cells. The expression of MALAT1 was examined by quantitative RT-PCR and normalized with GAPDH. The results are shown as mean ± SEM (n=3) and presented as fold change compared to DECKO targeting GFP control cells. ****p<0.0001 (unpaired student t-test).

1.ACS Appl. Bio Mater. 2021, XXXX, XXX, XXX-XXX

Publication Date:January 13, 2021


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