Overexpression of long noncoding RNA LINC01419 in esophageal squamous cell carcinoma and its relation to the sensitivity to 5-fluorouracil by mediating GSTP1 methylation

Abstract

Background: Genome-wide sequencing investigations have identified numerous long noncoding RNAs (lncRNAs) among mammals, many of which exhibit aberrant expression in cancers, including esophageal squamous cell carcinoma (ESCC). Herein, this study elucidates the role and mechanism by which LINC01419 regulates the DNA methylation of glutathione S-transferase pi 1 (GSTP1) in relation to ESCC progression and the sensitivity of ESCC cells to 5-fluorouracil (5-FU). Methods: LINC01419 and GSTP1 levels were quantified among 38 paired ESCC and adjacent tissue samples collected from patients with ESCC. To ascertain the contributory role of LINC01419 in the progression of ESCC and identify the interaction between LINC01419 and GSTP1 promoter methylation, LINC01419 was overexpressed or silenced, and the DNA methyltransferase inhibitor 5-Aza-CdR was treated. Results: Data from the GEO database (GSE21362) and the Cancer Genome Atlas displayed elevated levels of LINC01419 and downregulated levels of GSTP1 in the ESCC tissues and cells. The silencing of LINC01419 led to decreased proliferation, increased apoptosis, and enhanced sensitivity to 5-FU in ESCC cells. Notably, LINC01419 could bind to the promoter region of the GSTP1 gene, resulting in elevated GSTP1 methylation and reduced GSTP1 levels via the recruitment of DNA methyltransferase among ESCC cells, whereby ESCC progression was stimulated accompanied by reduced ESCC cell sensitivity to 5-FU. GSTP1 demethylation by 5-Aza-CdR was observed to reverse the effects of LINC01419 overexpression in ESCC cells and the response to 5-FU. Conclusion: Highly expressed LINC01419 in ESCC promotes GSTP1 methylation, which ultimately acts to promote the event of ESCC and diminish the sensitivity of ESCC cells to 5-FU, highlighting a novel potential strategy to improve 5-FU-based chemotherapy in ESCC.

Emerging Role of Non-Coding RNAs in Esophageal Squamous Cell Carcinoma

“…In ESCC, ncRNAs have been suggested to play roles as oncogenes or tumor suppressors to regulate ESCC proliferation, apoptosis, epithelial-mesenchymal transition (EMT), metastasis, chemotherapy, or radiotherapy [33][34][35][36][37]. Additionally, several ncRNAs have been observed to serve as prognostic markers in patients with ESCC [5,38]. Several studies which suggest the role and mechanism of ncRNAs in the development of ESCC have been summarized in Table 1.…”

“…Chemotherapy, radio-chemotherapy, and esophagectomy are the predominant therapeutic strategies for ESCC. However, the 5-year survival rate is still poor (<15%) [5,6]. Thus, it is of high importance to understand the pathogenetic mechanisms of ESCC and develop effective strategies to treat ESCC.…”

miR-454 suppresses the proliferation and invasion of ovarian cancer by targeting E2F6

“…Hypoxia is one of the important hallmarks of tumor microenvironment. Increasing studies have revealed that tumor hypoxia is closely related to the progression of cancer, such as tumor metastasis, recurrence and drug resistance [23][24][25][26]. It has been confirmed that hypoxia in vivo is associated with poor prognosis and high mortality in ovarian cancer patients, and involved in ovarian cancer cell proliferation [27,28].…”

miR-454 suppresses the proliferation and invasion of ovarian cancer by targeting E2F6

“…Hypoxia is one of the important hallmarks of tumor microenvironment. Increasing studies have revealed that tumor hypoxia is closely related to the progression of cancer, such as tumor metastasis, recurrence and drug resistance [25][26][27][28]. It has been con rmed that hypoxia in vivo is associated with poor prognosis and high mortality in ovarian cancer patients, and involved in ovarian cancer cell proliferation [29,30].…”