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. 2021 Sep 22;22(19):10201.
doi: 10.3390/ijms221910201.

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

Tsui-Lien Mao  1   2 , Ming-Huei Fan  3 , Nhlanhla Dlamini  4 , Chao-Lien Liu  3   4
Affiliations

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

Tsui-Lien Mao et al. Int J Mol Sci. .

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.

Keywords: cancer-associated fibroblast (CAF); chemoresistance; epithelial ovarian cancer (EOC); metastasis-associated lung adenocarcinoma transcript 1 (MALAT1); overexpression; tumorigenesis.

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Conflict of interest statement

The authors declare no competing interests with respect to this work.

Figures

Figure 1
Figure 1
Relative expression levels between MYST4 and MALAT1, and levels of MALAT1 in various types of human cancer tissues: (A) Relative expression levels between MYST4 and MALAT1 were detected by an RT-qPCR after MYST4-knockdown in the A2780, Skbr3, and Huh7 cell lines (* p < 0.05; ** p < 0.01; *** p < 0.001). (B) Relative expression levels between MYST4 and MALAT1 were measured using an RT-qPCR in the A2780, TOV112D, OVCAR3, HTB75, SKOV3, and TOV21G ovarian cancer (OC) lines and the P0 and P4 endometrial carcinoma cell lines. mRNA expressions were normalized by the level in HTB75 cells. (C) Correlated expression levels between MYST4 and MALAT1 in 26 ovarian carcinoma tissue samples were calculated using Pearson’s correlation analysis, but no significant correlations (r = 0.3175, p = 0.0997) between the two genes were found. (D) MALAT1 expression among 11 types of human carcinomas, including hepatocellular (HCC), cholangiolar, renal cell (RCC), lung, breast, ovarian, cervical, prostatic, colon, stomach, and pancreatic carcinomas by in-situ hybridization on tissue microarrays. Ovarian cancer (OC) showed the highest frequency of MALAT1 expression.
Figure 2
Figure 2
MALAT1 expression contributes to drug-resistance capacities. Effects of MALAT1 overexpression with (A) 1.0 μM CDDP alone, 1.2 nM PTX alone, or their combination in HTB75 cells, and (B) 1.2 μM CDDP alone, 1.2 nM PTX alone, or their combination in OVCAR3 cells were evaluated by cell viability assays after 12, 24, 36, and 48 h of drug treatment. Data shown were acquired from three independent experiments. ** p < 0.01.
Figure 3
Figure 3
Overexpression of MALAT1 enhanced HTB75 and OVCAR3 cell migration: Representative images of cell migration and their relative migration distances in (A,B) HTB75 and (C,D) OVCAR3 cell lines following transduced overexpression of MALAT1. Both MALAT1-overexpressing HTB75 and OVCAR3 cells showed significantly increased migration distances after a wound scratch at 24, 48, and 72 h compared to the mock-transduced (Mock) and non-transduced (Parental) controls (*** p < 0.001). The scale bar is 1 cm. Representative experiments were repeated at least three times.
Figure 4
Figure 4
Overexpression of MALAT1 increased the in vitro invasive capacity: Compared to mock-transduced (Mock) and non-transduced (Parental) cells, MALAT1-overexpressing (MALAT1) HTB75 (A,B) and OVCAR3 (C,D) cells showed significant increases in invasive cell numbers in the transwell invasive assay (**** p < 0.0001). Crystal violet-stained cells were captured after 12, 24, 36, and 48 h of incubation, and the scale bar shown is 1 cm (A,C). Line figures reveal the invasion cell numbers (B,D). Data are expressed as the mean ± SD. Similar results were obtained from three independent experiments.
Figure 5
Figure 5
Overexpression of MALAT1 in CAF02 fibroblasts induces OVCAR3 cell invasion: Representative (A) original levels of MALAT1 detected by an RT-qPCR analysis. (B,C) Changes in MALAT1 detected by an RT-qPCR analysis following transduction (D–H) overexpression of MALAT1 in CAF02 fibroblasts and OVCAR3 ovarian cancer (OC) cells respectively increased OVCAR3 cell invasive abilities (* p < 0.05; ** p < 0.01; *** p < 0.001). The experiment was repeated at least three times.
Figure 6
Figure 6
MALAT1 overexpression mediated epithelial ovarian cancer (EOC) progression through enhancing inflammation, cell proliferation, and metastasis, while reducing cell apoptosis: A schematic in vitro model for the overexpression of MALAT1 regulating different functional molecules with similar significance levels in both (A–C) HTB75 and (A–C) OVCAR3 cells through upregulation of IL-1β (*** p < 0.001), Cox2 (** p < 0.01 and *** p < 0.001, respectively), PGE2 (***p < 0.001), YAP (** p < 0.01), Vimentin (** p < 0.01), Cyclin D1 (* p < 0.05), Bcl2 (** p < 0.01 and *** p < 0.001, respectively), and zinc finger E-box-binding 2 (ZEB2) (** p < 0.01 and * p < 0.05, respectively), and downregulation of tumor necrosis factor (TNF)-α (* p < 0.05), interleukin (IL)-6 (** p < 0.01), and E-cadherin (** p < 0.01) mRNA levels by a real-time PCR analysis. Moreover, (D) protein levels of phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K) (*** p < 0.001 and * p < 0.05, respectively), p-Akt (** p < 0.01), p-P38 (*** p < 0.001), p-NFκB (*** p < 0.001 and * p < 0.05, respectively), and Bcl2 (* p < 0.05) were also significantly upregulated in MALAT1-overexpressing HTB75 and OVCAR3 cells by a Western blot analysis. (E) Functional mechanisms of MALAT1 overexpression in EOC samples include promotion of inflammation, cell proliferation, and metastasis, combined with inhibition of cellular apoptosis, thereby triggering tumor progression in EOCs. Data shown are the mean ± SD of three independent experiments.
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