|Year : 2022 | Volume
| Issue : 3 | Page : 545-550
|Linc-ROR promotes invasion and metastasis of gastric cancer by activating epithelial-mesenchymal transition
Mengyao Liu1, Mingkai Zhang2, Hongshan Yin3
1 Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
2 Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
3 Department of Urology, Binzhou Medical University Hospital, Binzhou, China
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|Date of Submission||06-Jul-2021|
|Date of Decision||23-Jan-2022|
|Date of Acceptance||30-Jan-2022|
|Date of Web Publication||21-Jul-2022|
| Abstract|| |
Introduction: Previous studies have shown that the long intergenic non-protein coding RNA regulator of reprogramming (linc-ROR) is abnormally expressed in a variety of malignancies and plays an important role in tumor progression. However, little is known about the role of linc-ROR in gastric cancer. In this study, the relationship between the expression of linc-ROR and clinicopathological factors in gastric cancer and its potential mechanism were explored. Materials and Methods: The cells were classified into two groups: ROR small interfering RNA(si-ROR) and the Negative control siRNA (si-NC).Linc-ROR was knockdown in si-ROR group by small interfering RNA (siRNA). Detect the expression of linc-ROR in gastric cancer tissues and normal tissues and its relationship with clinicopathologic characteristics by RT-PCR. the invasion ability was studied by wound healing assay and transwell assay. The expression levels of EMT-related molecules was detected by RT-PCR and Western blotting. Result: Showed that the expression of lincROR in gastric cancer tissues was significantly higher than that in the adjacent normal tissues. The lincROR expression level was significantly related to the tumor grade, lymph node metastasis, and TNM stage in cancer tissues. The lincROR knockdown in gastric cancer cell lines significantly inhibited cell invasion and metastasis. It affected its malignant biological behavior by activating the epithelial-mesenchymal transition through increasing expression of vimentin as well as decreasing E-cadherin levels in gastric cancer cells. The lincROR silencing significantly decreased the expression of β-catenin and c-myc. Conclusion: Linc-ROR can regulate cell invasion and metastasis by activating the epithelial-mesenchymal transition process partially through Wnt/β-catenin signal pathway in the gastric cancer cells. Link-ROR may be an important molecule for the metastasis of gastric cancer.
Keywords: Epithelial-mesenchymal transition, gastric cancer, metastasis, ROR
|How to cite this article:|
Liu M, Zhang M, Yin H. Linc-ROR promotes invasion and metastasis of gastric cancer by activating epithelial-mesenchymal transition. Indian J Pathol Microbiol 2022;65:545-50
|How to cite this URL:|
Liu M, Zhang M, Yin H. Linc-ROR promotes invasion and metastasis of gastric cancer by activating epithelial-mesenchymal transition. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:545-50. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/545/351615
| Introduction|| |
According to the latest Global Cancer Observatory (GLOBOCAN) database, gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality in the world. Due to the lack of early clinical manifestations, the majority of GC patients were in the advanced stage when the diagnosis was made. The overall survival rate of GC patients is low. Therefore, it is crucial to explore its molecular mechanisms for the metastasis of GC cells. In recent years, several genes related to the invasion and metastasis of GC and their regulatory mechanisms have become a hot research topic.
Only 2% of the genes in the human genome have the function of encoding proteins, and most of the human genome is composed of noncoding RNAs. Numerous pieces of literature have confirmed that noncoding RNA plays a key role in regulating cell function and disease development. The role of long noncoding RNAs (lncRNAs) in tumor progress has become a hot issue in the current research. LncRNAs are a class of RNA molecules (transcripts) that are more than 200 nt in length and have no coding protein function. Although lncRNAs have no function of encoding proteins, they can regulate the expression of the target genes involved in cell growth through genetic imprinting, chromatin modification, transcriptional activation, and interference. Linc-ROR is an important member of the lncRNAs family. In recent years, lncRNAs have been found to be dysregulated in a variety of tumor tissues, and are closely related to the pathogenesis and physiological processes such as tumor progression. It is suggested that it may be a novel molecular marker for tumor diagnosis and treatment.
Linc-ROR is a lncRNA with a length of 2.6 kb, which is located on chromosome 18q21.31, and contains four exons. The subcellular localization results show its expression in both the cytoplasm and nucleus. Linc-ROR promotes the proliferation and migration of esophageal cancer through regulating the MicroRNA-145 (miR-145) lamin B (LMNB) 2 signal axis and promotes proliferation, migration, and invasion via the Hippo/ yes-associated protein (YAP) pathway in the pancreatic cancer cells., Linc-ROR facilitates hepatocellular carcinoma resistance to doxorubicin by regulating Twist family bHLH transcription factor 1 (TWIST1)-mediated epithelial-mesenchymal transition. Linc-ROR promotes the resistance of radiotherapy in human colorectal cancer cells by targeting the P53/miR-145 pathway. However, the role of linc-ROR in GC development and progression is still undetermined.
In the present study, the relationship between the expression of linc-ROR and clinicopathological factors in GC and its potential mechanism were explored.
| Materials and Methods|| |
Patients and tissue specimens
Forty cases of matched tumor tissues and adjacent normal tissues were obtained from the GC patients who underwent radical gastrectomy at the Binzhou Medical University Hospital (Binzhou, Shandong province, China) from January 2016 to December 2017. All the patients did not receive local or systemic treatments before surgery. The tissues were immediately frozen in liquid nitrogen and reserved at –80°C for further analysis. All patients gave informed consent and the study was confirmed by the Human Research Ethics Committee of the Binzhou Medical University Hospital.
The SGC-7901 human GC cell line was purchased from the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences (Shanghai, China). The cells were cultured in Dulbecco's modification of Eagle's medium Dulbecco (DMEM) (HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum (HyClone, Logan, UT, USA), 100 U/mL penicillin, and 100 mg/mL streptomycin in a humidified incubator at 37°C with 5% CO2.
Small interfering RNA transfection
The cells were transfected using lipofectamine 2000 (Invitrogen, USA) according to the manufacturer's instructions. The small interfering RNA (si-RNA) targeting linc-ROR (5′-CCUGCAACAC UCCAGCUAUTT-3′, 5′-AUAGCUGGAGUGUUGCAGGTT-3′) and a negative control siRNA were purchased from the GenePharma Company, Shanghai, China. The cells were incubated for 48 h, and then, harvested for further assays.
After cell transfection at 48 h, the GC cells were seeded into six-well plates (5 × 105 cells/well). When the cells reached approximately 95% confluence, the cell layers were wounded using a sterile 200 μL pipette tip and washed with phosphate-buffered saline to remove cell debris. The cells were then cultured in a medium with 1% Fetal Bovine Serum (FBS). The scrape lines were photographed with a light microscope at the indicated time points. Each experiment was performed in triplicate.
Cell invasion assay
A cell invasion assay was performed using 24-well Matrigel invasion chambers (Corning Incorporated, Corning, NY, USA). After cell transfection at 48 h, 1 × 105 cells supplemented with free Fetal Bovine Serum (FBS) and medium were seeded on the upper chamber. Each bottom chamber was added 500 μL medium with 10% FBS. After 48 h, the cells in the bottom chamber were fixed with methanol and stained with 0.1% crystal violet, and then, counted using microscopy.
RNA extraction and quantitative real-time polymerase chain reaction (qRT-PCR)
The total RNA was extracted using TRIzol reagent (Invitrogen, Carlsbad, CA, USA). The total RNA was reverse transcribed into cDNA by a PrimeScriptTM RT reagent kit (TaKaRa, Japan) according to the instructions provided by the manufacturer. qRT-PCR was conducted by TB GreenTM Premix Ex TaqTMII (TaKaRa, Japan) on the Bio-Rad System (Bio-Rad, USA) according to the manufacturer's instructions. Moreover, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as an endogenous control. The sequences of primers (Invitrogen, USA) were designed as follows: Linc-RORprimers: 5′- GAAGGTT CA ACATGGAAACTGG-3′ and 5′- TGAGACCT GCTGATCCCATT C -3′.
E-cadherin primers: 5- CGAGAGCTACACGTTCACGG-3′ and 5- GGGTGTCGAGGGAAAAATAGG-3′. Vimentin primers: 5′- TGA CCTTGAACGCAAAGTGG-3′ and 5′- GAGGTCAGG CTTGGAAA CAT-3′. β-catenin primers: 5′- TG GTGACAGGGAAGACATCA-3′ and 5′ - CCATAGTGAAGGCGA ACTGC- 3′. c- myc primers: 5′ - GCCCAGTGAGGATATCTGGA-3′ and 5′- ATCGCAG ATGAAGC TCTGGT-3′. GAPDH primers: 5′-ACAGTCAGCCGCA T CTT CT – 3′ and 5′-GACAAGCTTCCCGTT CTCAG-3′. All the experiments were repeated in triplicate. The relative mRNA expression levels were normalized to GAPDH expression and were calculated using the 2−△△Ct method.
The transfected cells were harvested and lysed in lysis buffer supplemented with protease and phosphatase inhibitors (Solarbio, China), and the protein concentrations were detected using the BCA protein assay kit (Solarbio, China). Equal amounts of protein samples were electrophoretically separated on 8–15% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gels by molecular weight, and then, transferred to the Poly vinylidene fluoride (PVDF) membranes (Millipore, USA). After blocking in 5% skim milk in Phosphate Buffered Saline Tween-20 for 2 h at room temperature, the membranes were incubated with primary antibodies against E-cadherin (1:1000, Cell Signaling Technology, Boston, MA), vimentin (1:1000, Cell Signaling Technology, Boston, MA), β-catenin (1:4000, Proteintech, Chicago, IL, USA), c-myc (1:3000, Proteintech, Chicago, IL, USA), and GAPDH (1:4000, Proteintech, Chicago, IL, USA) overnight at 4°C. After washes with PBST, the membranes were incubated with Horseradish Peroxidase (HRP)-conjugated secondary antibodies (1:100,000, Jackson, Los Angeles, CA, USA) for 1 h at room temperature. Protein bands were detected using an enhanced chemiluminescence detection kit (Millipore, USA). Relative protein expression levels were measured using ImageJ software. Each test was performed at least three times.
SPSS 20.0 software (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 5.0 (GraphPad Software, La Jolla, CA, USA) were used for statistical analysis and the graphical presentation of data. Data were presented as mean ± SD. The statistical significance of the results was analyzed by the Student's t-test and one-way Analysis of Variance (ANOVA). The differences were considered statistically significant at P < 0.05.
| Results|| |
The expression of linc-ROR is higher in GC tissues
In our research, the relative expression level of linc-ROR was explored in 40 GC tissues and pair-matched adjacent normal tissues by RT-PCR and the results were normalized to GAPDH. The linc-ROR expression was significantly higher in 40 GC tissue samples compared with the adjacent normal GC tissue samples [Figure 1]a. In addition, a high expression of linc-ROR was significantly associated with a higher grade and later stages [Figure 1]b and [Figure 1]c. Meanwhile, the patients with lymph node metastasis had higher levels of linc-ROR expression than the patients without lymph node metastasis [Figure 1]d. However, no significant difference was observed between the linc-ROR expression and clinicopathologic characteristics, such as age, gender, tumor sizes, and location [Table 1]. These results indicate that the upregulated linc-ROR expression may be associated with GC development and tumor progression.
|Figure 1: (a) Linc-ROR expression was upregulated in gastric cancer. (a) Linc-ROR expression showed a significant difference between gastric cancer tissues (n = 40) and paired normal tissues (n = 40) by RT-PCR (P < 0.01). (b) Linc-ROR expression levels were significantly upregulated in patients with higher grades (P < 0.01). (c) Linc-ROR expression levels were markedly upregulated in patients with later stages (P < 0.01). (d) linc-ROR expression levels were markedly upregulated in patients with lymph node metastasis. Data are mean ± SD. *P < 0.05, **P < 0.01|
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|Table 1: The relationship between linc-ROR expression and clinicopathological factors in GC patients|
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Downregulation of linc-ROR inhibits cell invasion and metastasis of GC
The biological effects of linc-ROR on the invasion and migration of GC cells were studied. The wound-healing assay showed that the migration speed of cells in the si-ROR group was significantly slower than that in the si-NC group after knocking down the expression of linc-ROR in the SGC-7901 cells [Figure 2]. In addition, the transwell analysis showed that the reduction of linc-ROR expression in the SGC-7901 cells and the number of cells crossing the Matrigel in the si-ROR group was significantly less than in the si-NC group [Figure 3]. These results indicated that linc-ROR promoted the migration and invasion of GC cells.
|Figure 2: Effects of linc-ROR on the migration of GC cells. Silencing of linc-ROR inhibited the migratory ability of GC cells by wound-healing assay. **P < 0.01|
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|Figure 3: Effects of linc-ROR on the invasion of GC cells. Silencing of linc-ROR inhibited the invasive ability of GC cells by transwell invasion assay. *P < 0.05|
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Downregulation of linc-ROR suppresses the cell EMT process in GC cells
The Epithelial-Mesenchymal Transition (EMT) process of the tumor cells is considered one of the key factors leading to tumor metastasis. To investigate the oncogenic role of linc-ROR in GC EMT, we detected the EMT marker expression via RT-PCR and western blot. The results showed that the expression levels of vimentin in the si-ROR group were significantly downregulated when linc-ROR was specifically silenced in the SGC-7901 cells, while the expression levels of E-cadherin were upregulated compared with the si-NC group [Figure 4] and [Figure 5]a. These suggested that linc-ROR promoted EMT in SGC-7901 cells.
|Figure 4: The relationship between linc-ROR expression and EMT and Wnt/β-catenin signaling pathway by RT-PCR. Silencing of linc-ROR inhibited the EMT process and Wnt/β-catenin signaling pathway in GC cells by RT-PCR. Data are mean ± SD. *P < 0.05, **P < 0.01.|
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|Figure 5: (a) The relationship between linc-ROR expression and EMT by western blot. (b) The relationship between linc-ROR expression and Wnt/β-catenin signaling pathway by western blot. Silencing of linc-ROR inhibited the EMT process and Wnt/β-catenin signaling pathway in GC cells by western blot|
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Linc-ROR modulates Wnt/β-catenin signaling pathway in GC cells
We hypothesized that linc-ROR may activate the EMT process by regulating the Wnt/β-catenin signaling pathway in GC. The relationship between linc-ROR expression and the Wnt/β-catenin signaling pathway was analyzed by RT-PCR and western blot. Subsequently, the results showed that the expression of β-catenin and c-myc in the si-ROR group was significantly lower than that in the si-NC group [Figure 4] and [Figure 5]b. These results indicated that the silencing of the linc-ROR expression inhibits the transmission of the Wnt/β-catenin signaling pathway. Therefore, we concluded that linc-ROR promoted the EMT process in GC at least in part by activating the Wnt/β-catenin signaling pathway.
| Discussion|| |
GC is one of the most common malignancies in the world and poses a serious threat to human health. In recent years, despite many efforts in the diagnosis and treatment, the overall survival rate of patients with advanced GC, especially in cases with concurrent metastasis and recurrence, remains poor. Therefore, the specific mechanism for elucidating the metastasis and recurrence of GC is of great significance for improving the early diagnosis and the quality of life of patients with GC.
The human genome contains more than 50,000 lncRNAs that play a key role in maintaining cell and body homeostasis. With the deepening of research on lncRNAs, their important role in regulating diseases has gradually become well-known to researchers. A study has found that lncRNAs are involved in the progression of a variety of diseases. The underlying molecular mechanisms by which lncRNAs affect various biological processes, including chromatin organization, epigenetic regulation, gene transcription and translation, RNA turnover, and genome defense, have been reviewed extensively.
LINC01133 inhibits GC progression and metastasis by acting as a ceRNA for miR-106a-3p to regulate the adenomatosis polyposis coli (APC) expression and the Wnt/β- catenin pathway. LncRNA MT1JP regulates the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate the FBXW7 expression. LncRNA NEN885 can regulate cell migration and invasion by activating the epithelial- mesenchymal transition process partially through canonical Wnt/β-catenin signaling in the gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) cells.
The previous studies found Linc-ROR related to induced pluripotent stem cells. It has been involved in the self-renewal and dry maintenance of pluripotent stem cells and epithelial stem cells by preventing activation of the P53 signaling pathway. Subsequent studies have also shown that in addition to participating in the pluripotent stem cell self-renewal and dry maintenance, linc-ROR can also promote the resistance of various tumor cells to chemoradiotherapy by affecting the expression of pluripotent transcription factors such as Oct4, Sox2, and Nanog.
In recent years, linc-ROR has become new hot research in the field of noncoding RNA due to its special functions. It is abnormally expressed in various tumor tissues including esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, etc., playing a key role in regulating the progression of cancers., Linc-ROR promotes the invasion and metastasis of pancreatic cancer by inhibiting the activation of P53 and upregulating ZEB1 to induce EMT in the tumor cells. Linc-ROR induces EMT in the ovarian cancer cells by regulating the Wnt/β-catenin signaling pathway to promote ovarian cancer invasion and metastasis. In this study, our findings demonstrated that linc-ROR is overexpressed in the GC tissue compared to the adjacent normal tissues. A higher linc-ROR was associated with lymph node metastasis, poor differentiation, and advanced TNM stage in the GC patients. The cell invasion assays showed that the reducing expression level of linc-ROR can inhibit the invasion and migration of GC cells.
Tumor metastasis is a complex biological phenomenon, which is a highly selective, non-random process consisting of a series of interrelated and sequential steps. Among them, EMT transformation of the tumor cells is considered as one of the key steps leading to tumor metastasis., It is an important biological basis for the significant invasion and migration of malignant tumor cells derived from epithelial cells. Recent studies revealed that CHRF, DANCR, NR2F1-AS1, and other lncRNAs are involved in the EMT process of the tumor cells. E-cadherin and vimentin are the key regulators of the EMT process.,, Our present studies showed that Linc-ROR promoted cell invasion and migration in the GC cells through the EMT process.
The whole process of EMT is regulated by a variety of signaling pathways, and the Wnt/β-catenin signaling pathway is one of the important signaling pathways regulating EMT. Studies have confirmed that the Wnt/β-catenin pathway is critical to regulate biological characteristics such as cell growth, movement, and dry maintenance. As a key molecule of the Wnt/β-catenin signaling pathway, β-catenin can induce EMT transformation in the tumor cells by inhibiting the expression of E-cadherin, which ultimately leads to tumor metastasis and recurrence. We demonstrated that the knockdown of the expression of Linc-ROR in the GC cells downregulated the expression of c-myc and β-catenin, suggesting that linc-ROR can regulate the Wnt/β-catenin signaling pathway in GC.
In conclusion, the results of the present study revealed that the linc-ROR express level was elevated in the GC tissues and it promoted the invasion and metastasis of gastric cancer. Linc-ROR promoted malignant progression by initiating EMT in GC, and its specific mechanism may be achieved by acting on the Wnt/β-catenin signaling pathway. These findings indicated that linc-ROR was a potential biomarker and therapeutic target gene for GC.
The data could be available from the corresponding authors upon request.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We thank all the patients and our colleagues for their contribution.
Financial support and sponsorship
This work was supported by the Natural Sciences Fund of Shandong Province, China [grant numbers: ZR2019MH080].
Conflicts of interest
There are no conflicts of interest.
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Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, 256603
Source of Support: None, Conflict of Interest: None
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