LncRNA MALAT1 Facilitates Ovarian Cancer Progression through Promoting Chemoresistance and Invasiveness in the Tumor Microenvironment

Abstract

Upregulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2) or LINC00047) was found in various solid tumors, including epithelial ovarian cancer (EOC). MALAT1 is a long noncoding (lnc)RNA that regulates many functional signaling pathways, including tumorigenesis. Herein, we observed the consistent upregulation of MALAT1 in MYST4-overexpressing cell lines, while MALAT1 was frequently found to be upregulated in various types of clinical carcinoma tissues, especially EOC. To further investigate the lncRNA MALAT1 in EOC progression, the transduced overexpression of MALAT1 in EOC cell lines and cancer-associated fibroblasts (CAFs) was employed. We found that MALAT1 overexpression in EOC cell lines significantly increased drug resistance, cell migration, and invasion. Furthermore, the concomitant overexpression of MALAT1 in EOC cells and CAFs dramatically increased EOC cell invasion. Accordingly, a mechanistic investigation of MALAT1 overexpression in EOC cells showed that expressions of the cytokines interleukin (IL)-1β and p-P38/p-NFκB/Cox2/prostaglandin E2 (PGE2) signaling were significantly increased, which stimulated inflammatory responses, whereas cell apoptosis was inhibited due to increased Bcl-2 levels and reduced Caspase3 levels. After MALAT1 was overexpressed in EOC cells, and the cyclin D1, p-PI3K, and p-Akt expressions increased, suggesting the promotion of tumor cell proliferation, while increased zinc finger E-box-binding homeobox-2 (ZEB2), yes-associated protein (YAP), and vimentin expression with E-cadherin downregulation indicated the enhancement of the epithelial-to-mesenchymal transition (EMT) in terms of metastasis, thereby triggering EOC progression. Together, our findings demonstrate how MALAT1 overexpression facilitates an oncogenic function through inhibiting tumor cell apoptosis, combined with increasing tumor cell inflammation, proliferation, and invasion in the EOC tumor microenvironment. MALAT1 is thus a potential diagnostic marker and therapeutic for this malignancy.

Emerging role of lncRNAs in drug resistance mechanisms in head and neck squamous cell carcinoma

“…The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified as a prognostic factor in patients with lung cancer ( 151 ), and its overexpression is related to poor clinical outcome, chemoresistance, and progression in many cancer types, including kidney ( 152 , 153 ), pancreatic ( 154 ), prostate ( 155 , 156 ), esophageal ( 157 , 158 ), breast ( 159 , 160 ), gastric ( 161 ), ovarian ( 162 ), and colorectal ( 163 , 164 ). In both oral and laryngeal SCC, the over-expression of MALAT1 contributes to the enhanced chemoresistance and metastatic power of several cell lines ( 100 , 132 ).…”

Long noncoding RNAs as therapeutic targets to overcome chemoresistance in ovarian cancer

“…Overexpression of lncRNA MALAT1 led to promotion of cyclin D1, pAkt and p-PI3K, contributing to acceleration of ovarian cancer cell proliferation ( Mao et al, 2021 ). MALAT1 elevated the expression of IL-1β, p-P38, p-NF-κB, COX2 and PGE2 signaling, and reduced caspase-3 level and promoted Bcl-2 expression in ovarian cancer cells.…”

“…MALAT1 elevated the expression of IL-1β, p-P38, p-NF-κB, COX2 and PGE2 signaling, and reduced caspase-3 level and promoted Bcl-2 expression in ovarian cancer cells. MALAT1 upregulation also elevated the expression of ZEB2, YAP, vimentin and decreased E-cadherin, suggesting that MALAT1 triggered EMT and tumor metastasis in ovarian cancer cells ( Mao et al, 2021 ). Moreover, MALAT1 upregulation increased paclitaxel resistance of ovarian cancer cells in the tumor microenvironment ( Mao et al, 2021 ).…”

Derivation and Validation of a Necroptosis-Related lncRNA Signature in Patients with Ovarian Cancer

“…Along with the development of related researches, accumulating studies suggest that lncRNAs act as a vital role in development, progression, cell survival, and genesis of tumor [ 6 , 7 ]. Many lncRNAs are associated with drug response in various cancers, including OC [ 8 ]. To date, emerging evidence has shown the potential of lncRNAs in regulating necroptosis for cancer biology [ 9 ].…”