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Egyptian Journal of Medical Human Genetics
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Evaluation of the expression of the long non-coding RNAs, LOWEG and MINCR, and their clinical significance in human gastric cancer

Egyptian Journal of Medical Human Genetics volume 24, Article number: 87 (2023) Cite this article

Abstract

Background

Gastric cancer (GC) is currently the fifth most common malignancy. Accumulating evidence has recently revealed that maladjustments of diverse long non-coding RNAs may play key roles in multiple genetic and epigenetic phenomena in GC. Long non-coding RNAs (lncRNAs), which are transcriptional products with more than 200 nucleotides, are a subset of non-coding RNAs. LncRNA LOWEG and lncRNA MINCR, as novel lncRNAs, may have roles in GC progression.

Objective

This study aimed to examine the clinical and diagnostic significance of lncRNA LOWEG and lncRNA MINCR in GC.

Methods

The qRT-PCR technique measured lncRNA LOWEG and lncRNA MINCR expression in GC tissues and matched adjacent marginal tissues. The association between clinicopathological parameters and the expression level of lncRNAs was evaluated. Furthermore, The ROC curve was plotted to assess the diagnostic power of lncRNA LOWEG and lncRNA MINCR as candidate biomarkers in gastric cancer patients.

Results

We found that lncRNA LOWEG expression was downregulated in cancerous tissues compared to the adjacent marginal tissues (P-value < 0.0001). LncRNA MINCR expression was upregulated in cancerous tissues compared to adjacent marginal tissues (P-value < 0.0001). Downregulation of lncRNA LOWER and upregulation of lncRNA MINCR did not significantly correlate with clinicopathological parameters. ROC curve analysis showed that lncRNA LOWEG and lncRNA MINCR could be proposed as reliable diagnostic biomarkers in GC.

Conclusion

The expression of the lncRNA LOWEG was reduced in tumoral tissues compared to the adjacent marginal tissues, and the expression of lncRNA MINCR increased in tumoral tissues. So, as a result, lncRNAs LOWEG and MINCR could be considered diagnostic biomarkers for GC.

Introduction

Gastric cancer is the fifth most common cancer in the world and the third leading cause of cancer death [1]. This type of cancer is the most common gastrointestinal malignancy in parts of Asia, Central America, and South and Eastern Europe [2]. Out of 10,891,033 cases of gastric cancer in 2020 worldwide, 768,793 deaths due to this disease have been reported. The incidence of gastric cancer shows little difference from the resulting mortality rate, which is more due to the late diagnosis of gastric cancer in the advanced stages of the disease [3]. Gastric cancer is often discovered and diagnosed in advanced stages, and as a result, conventional therapies do not have a significant effect on increasing the life expectancy of patients. Recent advances in diagnosing and treating the disease have increased the long-term survival of patients with early-stage GC [4]. Identifying molecular, genetic, and epigenetic markers and new pharmacogenetic properties will improve diagnosis and treatment.

Non-coding RNAs are classified into short and long non-coding RNAs based on length. The cluster of short non-coding RNAs includes miRNAs, piRNAs, snoRNAs, and siRNAs. LncRNAs are a heterogeneous class of non-coding RNAs [5, 6]. LncRNA sequences are distributed across all chromosomes, covering about 90% of the human genome [7]. LncRNAs are approximately 200–100 kbps in length and, like mRNAs, are often produced by RNA polymerase II in combination with capping, splicing, and polyadenylation processes [8, 9]. Their genes also have regions for transcription factors (such as NF-KB) to bind to their promoter regions [10]. LncRNAs modulate gene expression by altering transcription levels, post-transcriptional modifications, and chromatin remodeling [11]. LncRNAs can also act as scaffolds for the assembly of two or more gene regulatory proteins and regulation of gene expression through miRNA uptake [12, 13]. LncRNAs are more abundant in the nucleus compared to mRNAs. They are cell-specific and are expressed in low levels. They also have fewer exons and shorter sequences than mRNAs [14, 15]. Studies show that lncRNAs have oncogenic or tumor-suppressive properties in developing cancers, including gastric cancer. Their improper expression can also lead to cellular changes and tumorigenesis in gastric cancer [16]. LncRNAs can be classified into the following subgroups based on the position of their genes on the genome: Intergenic, Intronic, Sense, Antisense, and Bidirectional [17, 18]. The lncRNA LOWEG, or CTD-2108O9.1 or EGFLAM-AS1, is 331 bp long and on human chromosome 5 (5p13.1). It was first identified in gastric cancer [19]. LncRNA LOWEG acts as a tumor suppressor gene that inhibits the invasion of tumor cells by regulating the expression of LIFR (leukemia inhibitory factor receptor) at the translational level in gastric cancer [19]. LncRNA MINCR (MYC-induced long non-coding RNA), also known as TCONS_00015189 or Long intergenic non-protein-coding RNA 1604, is an intergenic LncRNA located between two coding genes, GLI4 and ZNF696, on chromosome 8q24.3. It is also positively affecting the expression of MYC in MYC lymphomas [20]. MYC-induced lncRNA (MINCR) also can modulate the MYC (c-Myc) transcription network in Burkitt lymphoma cells. It can play an oncogenic role in cancers such as gallbladder cancer and liver cancer [21]. In this study, the expression level of lncRNA LOWEG and lncRNA MINCR was examined in GC tissues relative to the adjacent marginal tissues. The association between clinicopathological parameters and lncRNA LOWEG and MINCR expression levels was also addressed. The obtained information may shed more light on using lncRNA LOWEG and lncRNA MINCR as biomarkers in GC.

Materials and methods

Patient specimens

This study includes 100 gastric cancer patients referred to Valiasr Hospital in Tabriz, Iran, for surgery. Before performing the study, written consent was obtained from all patients. The Research Ethics Committee of the University of Tabriz confirmed the study. This investigation excluded GC cases undergoing radiotherapy, immunotherapy, or chemotherapy. The tissue samples were placed in liquid nitrogen (− 196 °C) until RNA extraction. The patient's clinicopathological data are presented in Table 1.

Table 1 Sequences of primers
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RNA isolation and real-time reverse transcription PCR

Total RNA was extracted from tissues using TRIzol reagent (RiboEx, GeneAll Biotech, Seoul, Korea, Cat. No. 301-001) according to the manufacturer’s instructions. After RNA extraction, its quantity and quality were evaluated by a NanoDrop device. RNA concentration was measured on NanoDrop (Thermo Fisher Scientific, USA), and the adsorption ratio was measured at 260–280 nm, followed by agarose gel electrophoresis. Reverse transcription reactions were performed using reverse transcripts of Rumi's mouse leukemia virus. RB cDNA synthesis Kit (RNA Biotechnology Company, Isfahan, Iran) was used to synthesize the first strand of cDNA from the extracted total RNA. cDNA was amplified using RealQ Plus 2 × Master Mix Green High ROX™ (Ampliqon, Denmark, Cat. No. A325402) in a qRT-PCR reaction. The sequence of primers is presented in Table 1. β-actin was used as the internal control to normalize the information of qRT-PCR. Each test was repeated two times, and the comparative expression of lncRNA LOWEG and lncRNA MINCR was figured out using method 2–ΔCT (Tables 2 and 3).

Table 2 LncRNA LOWEG expression and clinicopathological parameters of GC patients
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Table 3 LncRNA MINCR expression and clinicopathological parameters of GC patients
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Statistical analysis

Nonparametric tests were used to analyze the data. To statistically analyze the expression of lncRNA LOWEG and lncRNA MINCR genes in tumor tissue samples and tumor margins of gastric cancer after performing real-time PCR reactions, SPSS 26 software was used. Mann–Whitney test was used to analyze the differences between the data of the two groups. P-value < 0.05 was considered statistically significant. ROC curve analysis was performed using GraphPad Prism 9 software. This software was also used to evaluate a gene's potential to be considered a biomarker for the diagnosis or prognosis.

Results

The present study's first aim was to evaluate the expression of lncRNA LOWEG and lncRNA MINCR genes in GC tissues compared to non-cancerous control tissues. qRT-PCR was used to quantify the expression levels of lncRNA LOWEG and lncRNA MINCR in 100 pairs of GC cancer tissues and adjacent marginal tissues. Statistical analysis of the data showed that the expression of the lncRNA LOWEG gene in tumor tissues decreased compared to the tumor margin samples (CI = 95% and P-value < 0.0001, Fig. 1). Statistical analysis of the data also showed that the expression of the lncRNA MINCR gene in tumor tissues increased compared to the tumor margin samples (CI = 95% and P-value < 0.0001, Fig. 2).

Fig. 1
figure 1

LncRNA LOWEG expression in GC tissues as compared with marginal tissues (P-value < 0.0001)

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Fig. 2
figure 2

LncRNA MINCR expression in GC tissues as compared with marginal tissues (P-value < 0.0001)

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Examination of the ROC curves for both genes (lncRNA LOWEG and lncRNA MINCR) showed they could be introduced as reliable diagnostic biomarkers for gastric cancer (Figs. 3 and 4).

Fig. 3
figure 3

LncRNA LOWEG gene function as a diagnostic biomarker (area under the ROC curve = 0.75)

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Fig. 4
figure 4

LncRNA MINCR gene function as a diagnostic biomarker (area under the ROC curve = 0.77)

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The second aim was to determine the association between decreased lncRNA LOWEG expression. It increased lncRNA MINCR expression with clinical parameters such as age, gender, different tumor sizes, lymph node involvement, tumor stage, Helicobacter pylori infection, and Lauren type. The results showed no significant relationship between lncRNA LOWEG and lncRNA MINCR expression with clinical parameters.

Discussion

Gastric cancer is the third leading cause of cancer deaths in the world [22]. Gastric cancer is a heterogeneous disease, and different genes can play roles in its mechanism of development and progression [23].

In addition to protein-coding genes, it is approved that non-coding genes are also present in the human genome [24]. LncRNAs are a class of transcribed molecules that make up about 80% of non-coding RNAs. They are involved in several biological processes that can extend their regulatory activities in a trans or cis manner [25]. Improper expression of lncRNAs plays a vital role in tumorigenesis and metastasis of gastric cancer [26, 27]. LncRNAs can be used as diagnostic and prognostic biomarkers in gastric cancer [28]. For example, H19 is considered the most critical diagnostic solid biomarker for detecting early stages of gastric cancer. This molecule plays a vital role in tumor cell proliferation, metastasis, and invasion through various mechanisms such as mir-675 processing. [29]. Plasma overexpression of LINC00152 has been evaluated in gastric cancer patients, with a more excellent diagnostic value than CA1 and CEA. As a result, LINC00152 can be introduced as a robust diagnostic blood biomarker in gastric cancer [30].

The expression of lncRNA FENDRR is reduced in gastric cancer tissues. This molecule suppresses migration and invasion by inhibiting Fibronectin 1 and MMP2 / MMP9 [31]. Upregulation of lncRNA XIST through modulation of the miR-497/MACC1 axis promotes cell invasion and proliferation in GC [32]. LncRNA PVT1 inhibits the expression of tumor suppressor genes p15 and p16 and thus leads to cell cycle progression and cell proliferation [33]. High expression of lncRNA CCAT2 increases the MYC gene's expression, leading to increased expression of miR17HG and miR20a. These two molecules are essential in developing metastatic phenotype [34]. C-Myc can bind to the E-Box part of lncRNA CCAT1 in the promoter region, which leads to the upregulation of its expression in GC and its promotion to metastasis [35]. Several lncRNAs, such as HOTTIP, TUG1, and CCAT2, act as oncogenes, while some lncRNAs, such as ANRIL, MEG3, and GAS5, act as tumor suppressors [36]. MEG3 increases p53 expression by inhibiting p53-degrading MDM2 [37]. There is a new and extensive interactive system involving ceRNAs in which lncRNAs can act as miRNA sponges by separating miRNAs from their target mRNAs [38, 39]. LncRNA GAPCINC modulates CD44 by sponging miR-211-3p and increases metastasis [40]. LoxL1-AS1 modulates upstream stimulus factor 1 (USF1) to perform its oncogenic action in GC by sponging miR-708-5p [41].

The gene encoding lncRNA LOWEG is located in region 1 of the short arm of human chromosome number 5. LncRNA LOWEG prevents the invasion of tumor cells in gastric cancer by regulating LIFR expression at the translational level. LIFR can act as a metastasis suppressor by modulating the Hippo-YAP and the PTEN pathways [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]—the results of research by Zhao et al. In 2016, it was shown that lncRNA LOWEG increases LIFR expression, thereby preventing the invasion of gastric cancer cells by acting as a tumor suppressor [19] by Liao et al. In 2017, the expression pattern of lncRNA LOWEG in bladder cancer showed that the expression of lncRNA LOWEG in bladder cancer tissues is reduced compared to the healthy tumor peripheral tissues. Overexpression of lncRNA LOWEG also suppresses bladder tumors by inhibiting cell migration [37]. This study's results were consistent with our study's results on reducing lncRNA LOWEG expression in cancer cells compared to healthy tumor margins.

The gene encoding lncRNA MINCR is located in region 2 of the long arm of human chromosome 8 and between the genes encoding GLI4 and ZNF696. MINCR lncRNA can modulate the MYC transcription network in Burkitt lymphoma cells and inhibit apoptosis in cancer cells [20]—the research results by Chen et al. In 2019, lncRNA MINCR's expression increased in lung cancer tissues and cell lines, in which lncRNA MINCR had an oncogenic role [43]. Yang et al. showed that lincRNA MINCR activates the Wnt/β-catenin pathway by targeting the miR-708-5p/CTNNB1 axis and exacerbates colon cancer. They also showed that inhibition of lncRNA MINCR inhibited colon cancer cell proliferation, migration, and invasion [44]. The results of this study in connection with the increase of lncRNA MINCR expression in cancer cells compared to healthy cells peripheral to gastric cancer tumors confirmed the above results.

The fundamental molecular mechanisms of lncRNA LOWEG and MINCR are not yet recognized. Therefore, more studies are needed to discover their exact molecular mechanism.

Conclusions

The expression of the lncRNA LOWEG was reduced in tumoral tissues compared to the adjacent marginal tissues, and the expression of lncRNA MINCR increased in tumoral tissues. So, as a result, lncRNAs LOWEG and MINCR could be considered diagnostic biomarkers for GC.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Acknowledgements

All stages of this research were performed in the Molecular Genetics Laboratory of the Faculty of Natural Sciences, University of Tabriz. We are very grateful to the staff of Valiasr Hospital and the people who aided us in this study.

Funding

There was no funding.

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Authors and Affiliations

  1. Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, 29th Bahman Blvd., Tabriz, Iran

    Tooraj Ghasemzadeh, Ali Rajabi, Parisa Najari, Sama Akbarzadeh, Samaneh Tayefeh-Gholami, MohammadAli Hosseinpourfeizi & Reza Safaralizadeh

  2. Department of Plant Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Elaheh MalekAbbaslou

  3. Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Shahram Teimourian

Authors
  1. Tooraj Ghasemzadeh
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  2. Ali Rajabi
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  4. Parisa Najari
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  5. Sama Akbarzadeh
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  8. MohammadAli Hosseinpourfeizi
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  9. Reza Safaralizadeh
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Contributions

We declare that we contributed significantly toward the research study; MAH, AR, and RS designed the study and experiments. TG, EMA, PN, SA, and STG performed the experiments. TG and AR wrote the manuscript, and ST and RS revised the manuscript. AR and TG carried out the data analysis. All authors reviewed, considered, and approved the manuscript.

Corresponding author

Correspondence to Reza Safaralizadeh.

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Ethics approval and consent to participate

All patients signed written informed consent forms to allow their tissue specimens to be used in this project. This project was ethically authorized by the ethical committee of University of Tabriz, Tabriz, Iran (Approval Number: IR.TABRIZU.REC.1399.006).

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Not applicable.

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The authors declare no competing interests.

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Ghasemzadeh, T., Rajabi, A., MalekAbbaslou, E. et al. Evaluation of the expression of the long non-coding RNAs, LOWEG and MINCR, and their clinical significance in human gastric cancer. Egypt J Med Hum Genet 24, 87 (2023). https://doi.org/10.1186/s43042-023-00466-2

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