Research ArticleExperimental Studies
Open Access

LncRNA XIST Promotes Proliferation, Migration and Invasion of Esophageal Squamous Cell Carcinoma Cells via Regulation of miR-186-5p/ZEB1

YUNYUN MA, LILI QIAN, DECHAO WANG and CHANGYAN CHEN
Anticancer Research March 2025, 45 (3) 897-908; DOI: https://doi.org/10.21873/anticanres.17477

Abstract

Background/Aim: Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) are crucial molecules for tumor progression in various human cancers. However, the function of lncRNA X-inactive specific transcript (XIST) in esophageal squamous cell carcinoma (ESCC) remains to be determined. The current study aimed to explore the function and molecular mechanism of lncRNA XIST in ESCC progression.

Materials and Methods: The expression level of lncRNA XIST in ESCC cell lines was measured by qRT-PCR. The effects of lncRNA XIST on cell proliferation, migration, and invasion on ESCC were detected by CCK-8, transwell, and scratch assays. The expression levels of proteins were determined by western blot and luciferase reporter assays were used to identify specific target relationships.

Results: LncRNA XIST was overexpressed in ESCC cell lines when compared to normal cell lines. The inhibitor of lncRNA XIST markedly inhibited ESCC cell proliferation, migration, and invasion. Furthermore, miR-186-5p was down-regulated in ESCC cells. LncRNA XIST could sponge miR-186-5p and knockdown of lncRNA XIST could increase the expression of miR-186-5p. We also confirmed Zinc finger E-box binding homeobox 1 (ZEB1) as the target for miR-186-5p, while overexpression of ZEB1 reversed the effects of miR-186-5p inhibition on the malignant behavior of EC9706 and KYSE30 cells.

Conclusion: Our data revealed that lncRNA XIST promotes ESCC metastasis by regulating the miR-186-5p/ZEB1 axis. This study may provide a theoretical basis for the molecular mechanisms involved in esophageal cancer.

Keywords:

Introduction

Esophageal cancer (ESCA) is the eighth most common cancer and the sixth for mortality of all cancers worldwide (1). According to estimates from GLOBOCAN 2022, there were 544,000 esophageal cancer-related deaths globally in 2020, representing 5.5% of total malignant tumor-related mortalities (2). ESCA primarily consists of two major subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC is mostly found in Western countries, while ESCC accounts for more than 90% of ESCA and is distributed mainly through Asia, Eastern Europe, and Africa, especially in China (3-5). ESCA is a complex and heterogeneous disease, and its pathogenesis is related to ethnicity, genetics, and dietary intake (2-6). Despite the conventional approaches involving surgical resection, esophagectomy, chemotherapy, and radiation therapy the five-year survival rates for ESCC are still disappointingly low at approximately 15% (7-9). Therefore, it is crucial to understand its pathogenetic mechanisms and develop effective strategies for its treatment.

Long non-coding RNAs (lncRNAs) are a group of transcripts longer than 200 nucleotides and play essential roles in mediating cellular progression. In recent years, increasing evidence has revealed the important regulatory roles of lncRNAs in the occurrence and progression of different cancers, including ESCA (10, 11). Notably, the lncRNA-miRNA-mRNA regulatory axis widely participates in esophageal carcinogenesis (12). The irregular expression of lncRNAs has been associated with various facets of the biological characteristics of tumor cells. Thus, lncRNAs may represent attractive therapeutic targets in a variety of tumors (13, 14). LncRNA X-inactive specific transcript (XIST), a 19 kb lncRNA, is dysregulated in several cancers and is correlated with tumor progression (15-17). However, the exact role and the underlying mechanism of action of lncRNA XIST in the development of ESCC have not been fully investigated.

In this study, we confirmed the up-regulation of lncRNA XIST in ESCC providing evidence that lncRNA XIST may be able to sponge miR-186-5p, which in turn represses Zinc finger E-box binding homeobox 1 (ZEB1) expression, thereby contributing to the inhibition of ESCC tumorigenesis.

Materials and Methods

Cell culture and transfection. Human ESCC cell lines (EC9706, EC109 and KYSE30) and the human immortalized esophageal epithelial cell line SHEE were obtained from the Chinese Academy of Sciences Cell Bank (Wuhan, P.R. China) and cultured in Dulbecco’s Modified Essential medium plus 10% fetal bovine serum (Solarbio, Beijing, P.R. China) and maintained at 37°C with 5% CO2.

The miR-186-5p mimic, miR-NC, and miR-186-5p inhibitor were designed and synthesized by Sangon Biotech (Shanghai, P.R. China). The full sequence of ZEB1 was amplified and fused into the pcDNA-3.1 vector (Invitrogen, Carlsbad, CA, USA) to overexpress ZEB1 and cell transfection was carried out using Lipofectamine™ 2000 (Invitrogen), following the manufacturer’s protocol.

RNA extraction and qRT-PCR. Total RNA was extracted from cells using Trizol (Invitrogen) according to the manufacturer’s instructions. The RNA was transcribed to cDNA using a Reverse Transcription Kit (Takara, Dalian, P.R. China). qRT-PCR was performed with TaqMan Mix using an ABI 7500 fast real-time PCR system (Applied Biosystems, Darmstadt, Germany). GAPDH was employed as the internal control for lncRNA XIST and ZEB1, while U6 was used as a loading control for miR-186-5p. The primers for qRT-PCR were as follows: lncRNA XIST forward: 5′-AGC TCC TCG GAC AGC TGT AA-3′, reverse: 5′-CTC CAG ATA GCT GGC AAC C-3′ (18); ZEB1 forward: 5′-GTG ACG CAG TCT GGG TGT AA-3′, reverse: 5′-TGA GTC CTG TTC TTG GTC GC-3′ (19); GAPDH forward: 5′-GGG AGC CAA AAG GGT CAT-3′, reverse: 5′-GAG TCC TTC CAC GAT ACC AA-3′ (20); miR-186-5p forward: 5′-ACA CTC CAG CTG GGC AGC AGC ACA CT-3′, reverse: 5′-CTC AAC TGG TGT CGT GGA-3′ (21); U6 forward: 5′-GCT TCG GCA GCA CAT ATA CTA AAA T-3′, reverse: 5′-CGC TTC ACG AAT TTG CGT GTCA T-3′ (21). The qRT-PCR reactions were performed in triplicate and the relative expression of the RNAs was calculated using the 2−ΔΔCt method.

Cell proliferation assays. Cell proliferation was assessed using the CCK-8 assay (Dojindo, Tokyo, Japan), according to the manufacturer’s instructions. Cells were plated in 96-well plates at a density of 5×103/ml, grown at 37°C for 24 h, and then transfected with the corresponding vector. Finally, the absorbance was determined at 450 nm using a microplate reader (Bio-Rad, Hercules, CA, USA) and data were repeated at least three times.

Cell migration and invasion assays. Cell migration and invasion were detected using Transwell assays. After transfection, 5×104 cells were added into the upper chamber with polycarbonate micropores (Milipore, Bedford, MA, USA). After 24 h, cells were transferred to the bottom of the membrane and were fixed and stained with crystal violet. Scratch assays were then conducted on the cell layer which had been scratched by the pipette tip after transfection for 24 h. Images of the scratches were captured at 0 and 48 h.

Luciferase reporter assays. The 3′-UTR of lncRNA XIST containing a putative miR-186-5p binding site was cloned into a pmirGLO dual-Luciferase miRNA Target Expression Vector (Promega, Madison, WI, USA) to construct the wild-type (WT) luciferase reporter vector pmirGLO-XIST-WT. The same vector containing a mutated site of miR-186-5p in the lncRNA XIST sequence was also constructed (pmirGLO-XIST-MT). Luciferase reporter vectors pmirGLO-ZEB1-WT and pmirGLO-ZEB1-MT were also created using the same methods. Cells were transfected with luciferase reporter vector (pmirGLO), together with miR-186-5p mimic or miR-NC in 24 well plates. 48 h post-transfection, the luciferase activity was determined by the Dual-Luciferase Reporter Assay System (Promega) following the product manual.

Western blot. Total protein was extracted using a RIPA buffer containing a protease inhibitor cocktail (Abcam, Burlingame, CA, USA), followed by protein concentration analysis with a BCA protein assay kit (Pierce, Rockford, IL, USA). An equal quantity of protein was separated by SDS-PAGE and transferred to a PVDC membrane. Following blocking with 5% skimmed milk for 1 h, the membranes were incubated with primary antibodies at 4°C overnight with gentle shaking, followed by incubation with horseradish peroxidase secondary antibodies at room temperature for 1 h. The proteins in the membranes were visualized with the SuperSignal ECL kit (Pierce) according to the manufacturer’s instructions.

Statistical analysis. All statistical analyses were performed with SPSS 22.0 software (SPSS Inc., Armonk, NY, USA). GraphPad Prism 6.0 software (GraphPad, La Jolla, CA, USA) was used to construct the graphs. The data were presented as means±standard deviation (SD) and compared using Student’s t-test or one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test. Each assay was performed at least three times and p<0.05 was considered to be statistically significant.

Results

LncRNA XIST is up-regulated in ESCC cell lines. To explore the role of lncRNA XIST in ESCC progression, we first measured lncRNA XIST expression levels in three human ESCC cell lines (EC9706, EC109, and KYSE30) and one immortalized normal epithelial cell line (SHEE). Figure 1 shows that the expression of lncRNA XIST in ESCC cell lines was significantly up-regulated compared to that in the normal cell line.

Figure 1.
Figure 1.

Expression of lncRNA X-inactive specific transcript (XIST) is upregulated in esophageal squamous cell carcinoma (ESCC) cells. qRT-PCR results showed that lncRNA XIST expression levels were increased in ESCC cell lines [mean±standard deviation (SD), n=5]. *p<0.05, **p<0.01 and ***p<0.001 using one-way analysis of variance (ANOVA) followed by the Tukey-Kramer test.

Down-regulation of lncRNA XIST inhibits the proliferation, migration, and invasion of ESCC cell lines. Since lncRNA XIST was up-regulated in ESCC, we knocked it down in EC9706 and KYSE30 cells to explore its functional role. When lncRNA XIST was knocked down by si-XIST in EC9706 and KYSE30 cells, as expected, the expression level of lncRNA XIST was markedly reduced (Figure 2A). Under these conditions, a marked decrease in the viability of EC9706 and KYSE30 cells was observed (Figure 2B, C). Similarly, the results of the transwell migration and invasion assays showed that knockdown of lncRNA XIST led to decreased cell migration and invasion in EC9706 and KYSE30 cells (Figure 2D, E).

Figure 2.
Figure 2.
Figure 2.

Down-regulation of lncRNA X-inactive specific transcript (XIST) inhibits the proliferation, migration, and invasion of esophageal squamous cell carcinoma (ESCC) cells. EC9706 and KYSE30 were transfected with si-XIST or si-NC. (A) The knockdown efficiency of si-XIST was determined by qRT-PCR. (B, C) CCK-8 assays showed that knockdown of lncRNA XIST reduced the proliferation of EC9706 and KYSE30 cells. (D) Transwell assays showing the effect of lncRNA XIST suppression on EC9706 and KYSE30 cell migration. (E) Scratch assays showing the effect of lncRNA XIST suppression on EC9706 and KYSE30 cell migration. Data are shown as the mean±standard deviation (SD) (n=5). Scale bar: 100μm. *p<0.05, **p<0.01 and ***p<0.001 by Student’s t-test or one-way analysis of variance (ANOVA) followed by the Tukey-Kramer test.

LncRNA XIST interacts with miR-186-5p. Extensive evidence has shown that lncRNAs function as competitive endogenous RNAs (ceRNAs) capable of regulating a variety of biological processes. We used Starbase 3.0 (http://starbase.sysu.edu.cn/) and found that lncRNA XIST has a predicted targeting binding site for miR-186-5p (Figure 3A). To confirm this prediction, a luciferase reporter assay was performed in EC9706 cells. As expected, overexpression of miR-186-5p significantly reduced the luciferase activity of the reporter plasmids containing WT-lncRNA XIST, but not with MT-lncRNA XIST (Figure 3B). Furthermore, increased expression of miR-186-5p was observed after knockdown of lncRNA XIST in EC9706 and KYSE30 cells (Figure 3C). Moreover, using GEO2R (NCBI, MD, USA), data from the GEO database (GSE114110) revealed that miR-186-5p is down-regulated in ESCC tissues when compared to adjacent normal tissues (Figure 3D).

Figure 3.
Figure 3.

LncRNA X-inactive specific transcript (XIST) interacts with miR-186-5p. (A) Schematic diagram showing the predicted binding site between lncRNA XIST and miR-186-5p by Starbase. (B) Relative luciferase activities of wild type and mutated lncRNA XIST reporter in EC9706 cells transfected with miR-186-5p mimic. (C) The change in miR-186-5p levels after transfection with si-XIST in EC9706 and KYSE30 cells. (D) The results from the GEO database (accession number: GSE114110) show that miR-186-5p expression was down-regulated in esophageal squamous cell carcinoma (ESCC) tissues when compared to control tissues. Data are shown as the mean±standard deviation (SD) (n=5). *p<0.05 and **p<0.01 by Student’s t-test or one-way analysis of variance (ANOVA) followed by the Tukey-Kramer test.

LncRNA XIST promotes ZEB1 expression by sponging miR-186-5p. It is well established that miRNAs exert their multiple biological functions mainly by binding to the 3′-UTR of protein-coding genes thus regulating their expression. The binding sequence between ZEB1 and miR-186-5p was theoretically predicted using the TargetScan database (https://www.targetscan.org/vert_80/) (Figure 4A). To determine the relationship between miR-186-5p and ZEB1, the ZEB1 3′-UTR regions containing the WT binding site of miR-186-5p (WT-ZEB1), or the mutant binding site of miR-186-5p (MT-ZEB1) were inserted into the luciferase reporter vector. This assay showed that miR-186-5p inhibited the luciferase activity of WT-ZEB1 but had no effect on MT-ZEB1 (Figure 4B). Following western blot analysis, we found that the protein level of ZEB1 was suppressed after overexpression of miR-186-5p in EC9706 and KYSE30 cells (Figure 4C). Of note, the knockdown of lncRNA XIST markedly reduced the protein levels of ZEB1 in EC9706 and KYSE30 cells, and this effect could be reversed by the miR-186-5p inhibitor (Figure 4D). Furthermore, data from the GEPIA database (http://gepia.cancer-pku.cn/) revealed that ZEB1 was up-regulated in ESCA tissues when compared to normal tissues (Figure 4E). Together, these data suggest that lncRNA XIST up-regulates ZEB1 expression by acting as a ceRNA of miR-186-5p.

Figure 4.
Figure 4.

LncRNA X-inactive specific transcript (XIST) promotes Zinc finger E-box binding homeobox 1 (ZEB1) expression by sponging miR-186-5p. (A) Schematic diagram showing the predicted binding site between miR-186-5p and the 3′-UTR sequence of ZEB1 by TargetScan. (B) Relative luciferase activities of the wild type and mutated ZEB1 3′-UTR reporter in EC9706 cells transfected with miR-186-5p mimic. (C) The change in ZEB1 protein expression levels after transfection with miR-186-5p mimic or miR-186-5p inhibitor. (D) The change of ZEB1 protein expression levels after transfection with si-XIST alone or with the miR-186-5p inhibitor. (E) The results from the GEPIA database showed that ZEB1 expression was up-regulated in esophageal cancer (ESCA) tissues compared to normal tissues. Data are shown as the mean±standard deviation (SD) (n=4). *p<0.05 and **p<0.01 by one-way analysis of variance (ANOVA) followed by the Tukey-Kramer test.

Restoration of ZEB1 reverses the effects of miR-186-5p on ESCC cell proliferation and metastasis. In both EC9706 and KYSE30 cells, a marked reduction in cell viability was observed in cells transfected with miR-186-5p. However, this effect was blocked by overexpression of ZEB1 (Figure 5A, B). Likewise, miR-186-5p inhibited the migration and invasion capability of EC9706 or KYSE30 cells, and this action was also blocked by overexpression of ZEB1 (Figure 5C, D). Furthermore, miR-186-5p led to a marked inhibition of ZEB1 expression, which was reversed by the up-regulation of ZEB1 (Figure 5E).

Figure 5.
Figure 5.
Figure 5.

Restoration of Zinc finger E-box binding homeobox 1 (ZEB1) reverses the effects of miR-186-5p on esophageal squamous cell carcinoma (ESCC) cell proliferation, migration, and invasion. (A, B) CCK-8 assays show cell proliferation in the different transfected groups in EC9706 and KYSE30 cells. (C) Transwell assays showing the effects of EC9706 and KYSE30 cell migration in different transfected groups. (D) Scratch assay showing cell migration in the different groups on EC9706 and KYSE30 cells. (E) The change in ZEB1 protein expression levels after transfection with miR-186-5p mimic alone or with ZEB1. Data are shown as the mean±standard deviation (SD) (n=4). Scale bar: 100μm. *p<0.05, **p<0.01 and ***p<0.001 by one-way analysis of variance (ANOVA) followed by the Tukey-Kramer test.

Discussion

ESCC is a prevalent and deadly malignancy of the digestive tract, and many researchers have identified lncRNAs as crucial regulators during the pathogenesis of ESCC. Nevertheless, work investigating these RNAs in ESCC remains at an early stage, and further exploration is urgently required. In the current study, we explored the role of lncRNA XIST and its interaction with miR-186-5p via ZEB1 in ESCC progression. Our results showed that the down-regulation of lncRNA XIST suppressed the proliferation, migration, and invasion of ESCC cells through the miR-186-5p/ZEB1 axis, providing a novel therapeutic target for ESCC.

LncRNA XIST represents one of the first lncRNAs ever discovered in mammals and is essential for equilibrating gene expression between males and females during development (22, 23). However, accumulated evidence has shown that lncRNA XIST is dysregulated in numerous human cancers, and it is implicated in many aspects of carcinogenesis. Hu et al. (24) confirmed that lncRNA XIST can regulate cell migration, proliferation, and apoptosis in bladder cancer. A similar role for lncRNA XIST was also observed in breast cancer, colorectal cancer, lung cancer, osteosarcoma, and pancreatic cancer (25-29). Coincidentally, we confirmed that lncRNA XIST was up-regulated in ESCC cell lines. Functional studies have demonstrated that the down-regulation of lncRNA XIST caused a marked inhibition of ESCC cell proliferation, migration, and invasion. Furthermore, a previous study by others has shown that lncRNA XIST promoted the proliferation, migration, and invasion of TE-1 and SKGT-4 cells, suggesting that it may be a potent contributor to ESCC tumorigenesis (30).

Although lncRNA XIST has been documented to serve as an oncogenic factor in various malignancies, the exact mechanism by which lncRNA XIST promotes ESCC progression is still unclear. LncRNAs have been reported to affect tumorigenesis by multiple pathways. One suggestion is that lncRNAs function as ceRNAs by sponging miRNAs, thus affecting tumorigenesis (31). Here, we found that the lncRNA XIST sequence contains the putative binding sites of miR-186-5p using the Starbase 3.0 database. Moreover, accumulating evidence has indicated that miR-186-5p acts as a key regulator of tumorigenesis, involving ovarian cancer, colorectal cancer, glioblastoma multiforme, and osteosarcoma (32-35). MiR-186-5p was also considered to be an independent prognostic biomarker for esophageal cancer (36). Therefore, it needs to be determined whether miR-186-5p participates in lncRNA XIST-mediated promotion of ESCC growth. In this work, we found that miR-186-5p was down-regulated in ESCC tissues when compared to normal tissues from the GEO database and luciferase reporter assays suggested that lncRNA XIST functioned as a sponge for miR-186-5p in EC9706 cells and suppression of lncRNA XIST could promote the expression of miR-186-5p. This indicates that lncRNA XIST might exert its oncogenic function in ESCC via interaction with miR-186-5p.

To further explore the mechanism of action of lncRNA XIST in ESCC, we used the TargetScan software to predict the downstream targets of miR-186-5p and found that a miR-186-5p-binding site exists in the 3′-UTR sequence of ZEB1. ZEB1 is a zinc finger transcription factor that has been extensively studied in cancer for its purported role in driving metastasis, DNA damage response, and chemoresistance (37). Previous studies have reported aberrant expression of ZEB1 in a variety of human cancers (38). In vitro and in vivo observations revealed intrinsic oncogenic functions of ZEB1 that impact tumorigenesis from its earliest stages (39). In this work, we found that ZEB1 was up-regulated in ESCC and miR-186-5p expression was negatively correlated with ZEB1 expression in ESCC cell lines. Luciferase reporter assay identified ZEB1 as a direct target of miR-186-5p. Following our findings, ZEB1 was identified as a target of miR-186-5p in colorectal cancer and affects the proliferation metastasis, and EMT process of colorectal cancer cells (33). We further explored the role of ZEB1 in the lncRNA XIST-mediated promotion of ESCC growth and found that there was a positive correlation between lncRNA XIST and ZEB1 expression in ESCC cell lines. LncRNA XIST could regulate the expression of ZEB1 via targeting miR-186-5p, indicating that lncRNA XIST might affect ESCC progression via the miR-186-5p/ZEB1 axis. Furthermore, the combined results from EC9706 and KYSE30 cells, with ZEB1 overexpression, strongly suggested that restoration of ZEB1 could reverse the inhibitory effect of miR186-5p on ESCC cell proliferation, migration, and invasion. These data show a crucial role for lncRNA XIST/miR-186-5p in the regulation of ZEB1 in ESCC and provide a novel mechanism for its pathogenesis.

Conclusion

Our data provides the first evidence suggesting that up-regulated expression of lncRNA XIST can promote the malignant progression of ESCC by modulating the miR-186-5p/ZEB1 axis. Therefore, targeting lncRNA XIST/ZEB1 may be a novel strategy for a new therapy in ESCC.

Acknowledgements

We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Footnotes

  • Authors’ Contributions

    Yunyun Ma and Changyan Chen concepted and designed this study. Yunyun Ma, Lili Qian and Dechao Wang collected, analyzed, and interpreted the data. Yunyun Ma wrote the original draft. Changyan Chen reviewed and edited the manuscript.

  • Conflicts of Interest

    All the Authors declare no conflicts of interest regarding this study.

  • Funding

    This study was supported by the Key Scientific Research Projects of Colleges and Universities in Henan Province (22B310003).

  • Received January 1, 2025.
  • Revision received February 3, 2025.
  • Accepted February 5, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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LncRNA XIST Promotes Proliferation, Migration and Invasion of Esophageal Squamous Cell Carcinoma Cells via Regulation of miR-186-5p/ZEB1
YUNYUN MA, LILI QIAN, DECHAO WANG, CHANGYAN CHEN
Anticancer Research Mar 2025, 45 (3) 897-908; DOI: 10.21873/anticanres.17477
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