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.
Highlights
Regulation of lncRNAs has attracted crucial interest in omics studies in recent years, yet there are still varying opinions as to how these functionally conserved transcripts of more than 200 nucleotides drive tumorigenesis
Through an analysis of MYST4 gene knockdown in cancer cell lines in multiple organs, including the A2780 ovarian cancer cell line, Skbr3 breast cancer cell line, and Huh7 hepatoma cell line, we found significant reductions in metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) levels in the three MYST4-knockdown tumor cell lines compared to their respective parental cells (Figure 1A; * p < 0.05, ** p < 0.01, and *** p < 0.001; Figure S1)
Applying in vitro experiments using clinical cancer tissues and cancer cell lines, we observed that overexpression of the lncRNA MALAT1 in epithelial ovarian cancer (EOC) cells encouraged drug resistance, invasion, and migration through adaptive remodeling strategies that promote tumor cell survival and proliferation, combined with the inhibition of cellular immunity and apoptosis in the tumor microenvironment (TME), triggering EOC tumor progression
Summary
Regulation of lncRNAs has attracted crucial interest in omics studies in recent years, yet there are still varying opinions as to how these functionally conserved transcripts of more than 200 nucleotides (nt) drive tumorigenesis. These conserved transcripts of noncoding DNA sequences contribute to multiple signaling pathways and functionally interact with many different genes [1]. MALAT1, a nuclear-restricted housekeeping regulatory lncRNA located on chromosome. Epithelial ovarian cancer (OC; EOC) is one of the lethal gynecological cancers, with evidence that lncRNAs participate in tumorigenesis [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
