Long Non-Coding RNAs as Strategic Molecules to Augment the Radiation Therapy in Esophageal Squamous Cell Carcinoma

Abstract

Intrinsic resistance to ionizing radiation is the major impediment in the treatment and clinical management of esophageal squamous cell carcinoma (ESCC), leading to tumor relapse and poor prognosis. Although several biological and molecular mechanisms are responsible for resistance to radiotherapy in ESCC, the molecule(s) involved in predicting radiotherapy response and prognosis are still lacking, thus requiring a detailed understanding. Recent studies have demonstrated an imperative correlation amongst several long non-coding RNAs and their involvement in complex cellular networks like DNA damage and repair, cell cycle, apoptosis, proliferation, and epithelial-mesenchymal transition. Additionally, accumulating evidence has suggested abnormal expression of lncRNAs in malignant tumor cells before and after radiotherapy effects in tumor cells' sensitivity. Thus, lncRNAs indeed represent unique molecules that can influence tumor cell susceptibility for various clinical interventions. On this note, herein, we have summarized the current status of lncRNAs in augmenting resistance/sensitivity in ESCC against radiotherapy. In addition, we have also discussed various strategies to increase the radiosensitivity in ESCC cells under clinical settings.

Keywords: esophageal squamous cell carcinoma; long non-coding RNAs; radioresistance; radiosensitivity; radiotherapy.

Figure 1

Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow chart describing the process of literature search and study selection related to esophageal squamous cell carcinoma (ESCC) and radioresistance/radiosensitivity. The total number of 11 relevant research articles were included in the review.

Figure 2

Schematic illustration of the molecular mechanisms of lncRNAs in the regulation of radioresistance in ESCC treatment. After radiation exposure to the ESCC cells, increased expression of FOXO1 transcribes the lncRNA DNM3OS by binding to its promoter region. Moreover, the increased expression of DNM3OS suppressed the levels of double-strand break proteins, such as H2A histone family member X (γH2AX) protein and cleaved poly ADP ribose polymerase (PARP) followed by increased levels of DNA repair enzymes, such as pATM, Rad50, phosphorylated checkpoint kinase 2 (pChk2), Ku80, meiotic recombination 11 homolog 1 (MRE1), Nijmegen breakage syndrome 1 (NBS1), DNA protein kinase (DNA-PKcs), and ultimately promote ESCC cell DNA repair. After radiation exposure to the ESCC cells, SPIN1, miR-374-5p, and miR-497-5p demonstrated competitive binding to upregulated lncRNA LINC00473. Moreover, miR-374-5p and miR-497-5p was suppressed after binding to the LINC00473, which is followed by the upregulated expression of PARP and Cdc25A, respectively, which are ultimately unable to break the double-strand DNA of ESCC cells. After radiation exposure to the ESCC cells, miR-615-5p competes for its binding to the upregulated lncRNA LINC00657. Moreover, the expression of miR-615-5p was suppressed after binding to the LINC00657, which is followed by the upregulated expression of JunB, which ultimately promotes the double-strand DNA repair of ESCC cells. After radiation exposure to the ESCC cells, POU6F2-AS1 expression was increased, which further recruits Ybx1 to the promoters of cyclin B1 (CCNB1) and p53 gene and the DNA damage sites and thus increases the Ybx1 protein levels, which ultimately promotes ESCC cell DNA repair.

Figure 3

Schematic illustration of the molecular mechanisms of lncRNAs in the regulation of radiosensitivity in ESCC treatment. After radiation exposure to the ESCC cells, miR-101 binds to downregulate lncRNA FAM201A. Moreover, the expression of miR-101 was increased after binding to the FAM201A, which is followed by downregulated expression of mTOR and ATM, which decreases the homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway and thus promotes the breakdown of double-strand DNA of ESCC cells. After radiation exposure to the ESCC cells, MALAT1 expression was decreased, which further inhibits Cks1 levels at both mRNA and protein levels. In addition, it also decreased YAP’s translational activity, reducing the expression levels of connective tissue growth factor (CTGF), thus enhancing the breakdown of the double-strand DNA in ESCC cells. After radiation exposure to the ESCC cells, downregulated expression of lncRNAs LOC285194 and AFAP-AS1 inhibits DNA repairing of ESCC cells. After radiation exposure to the ESCC cells, miR-144-3p competes with binding to the downregulated lncRNA TUG1. Moreover, the expression of miR-144-3p was increased after binding to the TUG1, which is followed by downregulated expression of c-MET, EGFR, and p-Akt protein, which ultimately promotes the breakdown of double strand DNA of ESCC cells and confers radiosensitivity.