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Evaluation of the Rock1 and microRNA-148a expression in biopsies collected from patients with Helicobacter pylori induced gastritis

BMC Gastroenterology volume 24, Article number: 251 (2024) Cite this article

Abstract

Background

Helicobacter pylori infection is one of the most common chronic bacterial infections, especially in developing countries. MicroRNA-148a is involved in the regulation of various genes, including Rock1, which is altered in gastric cancer. Decreased expression of mir-148a leads to tumor metastasis and increased Rock1 gene expression in gastric cancer. This study aimed to investigate the expression of these genes in biopsies collected from patients with H. pylori induced gastritis.

Methods

Informed consent forms were gotten from the studied patients with gastritis who needed endoscopy. Gastric biopsies were taken by a gastroenterologist from patients with inflammation. Rapid urease test, stool antigen detection, and histopathological staining were used to determine the H. pylori infected patients. Real time PCR was used to evaluate the miRNA and Rock1 expression levels.

Results

The Rock1 expression level in biopsies that were positive for H. pylori was significantly increased compared to our control gastritis group that were H. pylori-negative, but the results were not statistically significant. Moreover, the mir-148a expression level in H. pylori-positive patients with gastritis was increased compared to our control group. However, the results were not statistically significant. We did not find a significant relation between the expression levels of Rock1 and mir-148a in samples with gastritis infected or uninfected by H. pylori. This result may be due to the small sample size.

Conclusion

We suggest that this test should be carried out with more samples, and the comparison should be done between biopsies with inflammation and no inflammation in a patient.

Peer Review reports

Background

Helicobacter pylori is a gram-negative microaerophilic bacillus inhabitant in the human gastric mucosa, causing infections, especially in developing countries [1]. Humans are the natural reservoir of H. pylori, and it has been shown that this organism plays an important role in the pathogenesis of the gastric and duodenal ulcers, mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, and gastric cancer [2, 3]. Chronic H. pylori infection may be associated with chronic gastritis, MALT-B-cell lymphoma, and gastric adenocarcinoma [2,3,4].

On the other hand, changing in the expression of genes controlling the growth and proliferation of cells can affect the cell function and increase the risk of cells entering the uncontrolled growth phase [5]. Micro-RNAs are evolutionarily small non-coding RNAs (ncRNAs) that regulate the eukaryotic cell gene expression after transcription, and alter the production of various cellular proteins [6]. Following infection with H. pylori, a change in the microRNAs’ expression may be observed, resulting in a significant effect on their target proteins and cellular pathway [7]. Depending on the type and activity of the target proteins, the miRNAs can be designated as tumor inhibitors or oncogenes [6]. Under the normal physiological conditions, the mir-148a gene is expressed in various human tissues, including the brain, heart, liver, thymus, pancreas, kidney, the placenta, uterus, testicles, hematopoietic system, and normal gastric tissues [8]. Moreover, the mir-148a high expression level can regulate the maintenance of gastric tissue stability, while its abnormal expression may cause gastric neoplasms [8]. It is also involved in the regulation of various genes expressed in gastric cancers, including ROCK1, BCL2, APC, P53, BRCA1 and BRCA2 [9,10,11,12,13]. Decreased expression of mir-148a can lead to tumor metastasis and increased expression of Rock1 gene in gastric cancer, and its high expression prevents the invasion and migration of gastric cancer cells in vitro [8, 9].

The hallmark of cancer cells is ability to invade adjacent tissues that requires increased cell motility due to the skeletal system renewal and cell contact with the extracellular matrix (ECM) [8]. The ROCK (Rho-associated coiled-coil kinase) family proteins consist of the small GTPases, including Rho, Rac, and Cdc42, and can regulate the structural organization of the actin cytoskeleton and cellular homeostasis [9, 14]. The Rock1 contributes in contraction, adhesion, migration, metastasis, angiogenesis, and proliferation of the cancer cells, and has an anti-apoptosis effect [9, 14]. The Rock1 gene is located on chromosome 18, and the ROCK1 protein is activated after binding to RhoA in GTP, resulting in the cytoskeleton regulation [9, 14]. Increased expression of this protein has been observed in nasopharyngeal carcinoma and non-small cell lung, breast, and gastric cancers, makes them more aggressive [8, 9, 15]. The role of miRNAs and ROCK1 should be investigated in various cancer processes. Thus, we aimed to evaluate the expression levels of these genes in biopsies collected from patients with gastritis in patients infected with H. pylori compared to the H. pylori-negative patients with gastritis.

Methods

Ethical approval statement and consent of participants

First, a printed informed consent form was provided by the patients with gastric inflammation. The clinical samples of patients were taken by a qualified gastroenterologist in an endoscopy center affiliated with the Mazandaran University of Medical Sciences. This study was done according to the Declaration of Helsinki, and the categorizing data of patients was kept secret. Moreover, this research was approved by the Iran National Committee for Ethics in Biomedical Research with the national ethical code IR.MAZUMS.REC.1397.382.

Sample collection and detection of bacterial infection

We received three gastric biopsies. One sample was used for the rapid urease test (RUT) using a urea broth culture media (Merck, Germany) at the patient’s bedside. One biopsy was aseptically transported to the microbiology laboratory for RNA extraction. This biopsy was transferred in a micro tube containing RNA stabilization solution (DNAbiotech, Iran) at 4 °C and stored overnight, and then frizzed at -80 °C until use. The remaining biopsy was transported to the pathology center for the staining. We used the Giemsa staining to detect H. pylori as follows: 1- immersion the slides in xylene 1, 2, and 3 (each for 2 min), 2- immersion in absolute alcohol 1 and 2 (each for 2 min), 3- ten times immersion in each 96% and 70% alcohol, 4- rinsing with distilled water and putting in a Giemsa solution overnight, 5- rinsing with distilled water and 0.5% acetic acid, and 6- washing with running water and dry in air. Also, a stool antigen detection test by the rapid strip (Mascia Brunelli, Italy), according to the manufacturer’s instructions, was used to confirm the H. pylori infection. The gold standard in the present study was the pathology test. However, a stool antigen detection test was used to detect the positive samples that we did not detect the bacteria, or the samples with the weak positive result.

RNA extraction and cDNA synthesis

We cut the biopsies as far as possible with a sterile razor blade and crushed them by a sterile tip. Then, the total RNAs were extracted from the gastric biopsies collected from patients with gastritis using a RNA extraction kit (Wizbiosolutions, South Korea), according to the manufacturer’s instructions. Also, the cDNA synthesis was done using a cDNA synthesis kit (Wizbiosolutions, South Korea), according to the manufacturer’s instructions. To synthesis the cDNA specific for miRNA, we used a steam loop primer designated as previously reported [16], and the U6 specific primer was used to synthesis the cDNA specific for the U6 internal control gene [17]. However, for synthesis the cDNA specific for the Rock1, the Random hexamer and Oligo (DT) primers were used in this study. All primer sequences are shown in Table 1.

The cDNA synthesis procedure was as follows: 5 µl of the extracted RNA, 4 µl of 5x first-standard buffer (Wizbiosolutions), 1 µl of dNTP (10 mM) (Wizbiosolutions), 0.5 µl RNase inhibitor (40 U/µl) (Wizbiosolutions), and 1 µl of M-MLV (Wizbiosolutions) were added to the volume of 20 µl with DEPC treated water (Wizbiosolutions). We used a thermal cycler (BioRad, USA) for the cDNA synthesis as follows: (a) 42 °C for 60 min, (b) 70 °C for 5 min for Rock1 and 10 min for miRNA and GAPDH (glyceraldehyde 3-phosphate dehydrogenase), and (c) 4 °C for further storage. To determine the accuracy of the products, we measured the optical density (OD) of the products at a wavelength of 260/280 nm by a NanoDrop spectrophotometer (ND-1000, USA) and electrophoresed the products on a 2% agarose gel (SinaClon, IRAN). Finally, the RNAs and cDNAs were stored at -80 °C until use.

Quantitative real-time (qRT-PCR) PCR

The Real-time PCR using the SYBR premix EX TaqII, Tli RNaseH plus (Takara Bio Inc., Japan) was used to analyze the expression of Rock1 and miRNA-148a genes compared to the GAPDH normalizing housekeeping gene. This test was done in duplicate runs by an Applied Biosystems 7500 Real-Time PCR machine (Thermo Fisher Scientific, USA). The specific primers used to the amplification of the target genes in this study are shown in Table 1. The U6 gene was used as a normalizing gene in the real-time PCR for evaluation of the expression level of miRNA, and the GAPDH gene was considered as a normalizing gene for the assessment of the Rock1 expression. The U6 is a highly conserved small non-coding RNA (snRNA) and a major component of the spliceosome in the processing of mRNA precursors [18].

The real-time PCR reaction was performed in a final volume of 15 µl. The final concentration of primers in all reactions was 10 pmol and the final concentration of cDNA in all reactions was 100 ng. The reaction conditions for the amplification of miRNA148a and Rock1 were included an initial denaturation at 95 °C for 2 min and 45 cycles of two step PCR, including 15 s at 95 °C and 50 s at 58 °C. The melting curve was drawn from 58 °C to 95 °C. The amplification of the GAPDH and U6 genes were also carried out in the same condition. A reaction without cDNA (no template control) was used as a negative control. The gene expression levels of the cases (gastritis with H. pylori) compared to the controls (gastritis without H. pylori) were calculated according to a previously described relative quantification method (2−ΔΔCt method, Livak, and Schmittgen, 2001) [19].

Table 1 The primer sequences used in this study
Full size table

Statistical analysis

Data analysis was performed using the processes applied in GraphPad Prism software version 7. The data were compared with independent T-test, and P-value < 0.05 was considered statistically significant.

Results

The gastroenterologist responsible for sampling in our study did the endoscopy on suspected patients and performed sampling as soon as signs of inflammation were observed. In the present study, 37 biopsies were collected from patients with inclusion criteria to gain 25 H. pylori-positive samples. Also, 78 biopsies were collected from patients with inclusion criteria to obtain 25 H. pylori-negative samples. A 67.56% prevalence of H. pylori was detected in this study. Some results of the pathology test are shown in Fig. 1.

Fig. 1
figure 1

The results of pathology test in this study

Groups A, B, C, and D are shown the negative results for H. pylori detection in Giemsa staining method. Groups E and F are weak positive samples, while G and H are shown the samples with a strong positive result.

Full size image

In addition, the fold change expressions of the target genes and the pathology results of the H. pylori-positive and –negative biopsies are shown in Tables 2 and 3. According to these tables and the results of the pathological staining, 25 biopsies were positive for the presence of H. pylori, and others were negative.

Table 2 The real-time PCR results of H. Pylori-positive samples
Full size table
Table 3 The real-time PCR results of H. Pylori-negative samples
Full size table

According to two-tailed independent T-test, the Rock1 expression in samples infected by H. pylori was 7.96 times more than the specimens with gastritis but H. pylori-negative (P-value = 0.095) (Fig. 2). Also, the miRNA-148a expression in H. pylori-positive samples was 2.8205 times more than the H. pylori-negative samples (P-value = 0.406) (Fig. 3). However, there was no significant difference between the expression of two genes and the presence of H. pylori.

Fig. 2
figure 2

Comparison of rock1 expression level in H. pylori-positive and H. pylori-negative samples collected from patients with gastritis

Full size image
Fig. 3
figure 3

Comparison of mir-148a expression level in H. pylori-positive and H. pylori-negative samples collected from patients with gastritis

Full size image

According to the analysis of the expression level of the mir-148a and Rock1 genes among the biopsy samples with the same pathological profile, we found that the average expression of the mir-148a gene in H. pylori-negative biopsies with chronic moderate pathology profile was 2.77 times more than that of H. pylori-positive biopsies with the same pathology (P-value = 0.048). Meanwhile, the average expression of the Rock1 gene in H. pylori-positive samples was 65.43 times more than the H. pylori-negative biopsies (P-value = 0.000). Also, the average expression of mir-148a gene in H. pylori-negative biopsies with chronic mild pathology result was 14.81 times more than that of H. pylori-positive samples (P-value = 0.015), while the average expression of Rock1 gene in H. pylori-positive biopsies was 53.35 times more than the H. pylori-negative samples (P-value = 0.000).

Discussion

Helicobacter pylori can cause gastritis, gastric or duodenal ulcers, and rarely gastric lymphoma or gastric cancer [21]. However, the gastric cancer is considered as the second cause of cancer-related death [9, 21]. On the other hand, the microRNAs are a group of non-coding small RNAs containing 19–25 nucleotides located in the introns of genes [8, 9, 21]. Different miRNAs can mediate the regulation of various genes, resulting in development, proliferation, differentiation, and/or apoptosis of the cells [8, 9]. Deregulation of some miRNAs is observed in patients with cancers, however, miRNA-148a is downregulated in gastric cancers [9]. Human invaded cells can recognize the invading pathogens or their secreted virulence factors by the receptors, resulting in the innate immune activation followed by the specific immunity [21]. Some molecular bridges between two immune systems are the potential bridge between the inflammation and cancers [21]. However, the ROCK1 is a potential protein that contributes in contraction, adhesion, migration, metastasis, angiogenesis, and proliferation of cancer cells, and has an anti-apoptosis effect [9, 14]. The miR-148a can inhibit some cancer cells proliferation and metastasis by downregulation of the Rock1 gene [8, 9, 14, 21]. Since the H. pylori can cause chronic inflammation followed by gastric cancers [21], the assessment of mir-148a and Rock1 expression levels in patients with gastritis and infected by H. pylori was aimed in this study.

The results of the present study showed that the expression of Rock1 gene in H. pylori-positive patients with gastritis was increased (7.96 times) compared to the H. pylori-negative patients but was not statistically significant. (P-value = 0.095). Also, mir-148a expression was increased in H. pylori-positive patients with gastritis (2.8205 times) compared to the H. pylori-negative patients but this increase was not statistically significant (P-value = 0.406). This may be due to the small sample size of the present study and the patients who had a gastritis. To solve this problem, we analyzed the expression level of these genes among samples with the same pathology results and found that the average expression of the mir-148a gene in H. pylori-negative biopsies with chronic or mild moderate pathology profile was significantly more than that of H. pylori-positive biopsies (P-value˂0.05). Also, the average expression of the Rock1 gene in H. pylori-positive samples with chronic moderate or mild pathology profile was significantly more than the H. pylori-negative biopsies (P-value = 0.000). These results indicate the importance of the mir-148a gene in controlling the expression of the Rock1 gene in H. pylori-negative patients. However, other studies that observed a significant relation between the expressions of these genes were done on samples collected from patients with cancers [22,23,24,25,26].

According to various reports, different types of microRNAs, including mir-21, mir-378, mir-146a, mir-370, and mir-72-76 are involved in H. pylori infection, resulting in gastric cancer [24, 27,28,29]. However, Chen et al. reported a decreased expression of mir-148a and mir-152 in cancerous tissues compared to the adjacent normal tissues [24]. Low expression of mir-152 was associated with increased tumor size and stage but low expression of mir-148a was associated with increased tumor size [24]. This decreased expression of the mir-148a in tumoral tissues may justify the insignificance of our results. However, the mir-148a may not has significant decreased expression in the proinflammatory stage. The mir-148a and mir-146a can inhibit the progression of pancreatic, breast, and gastric cancers by inhibiting the increased expression of EGFR, CXCR4, IRAK1, and Rock1 genes [8, 9]. As the ROCK1 can inhibit the cell death and increases the lifespan of cancer cells, this results in the cell longevity due to loss of cellular polarity [8, 9, 14, 16]. The amoebic invasion of tumor cells is dependent on the Rho/Rock proteins that play an important role in cancer progression, metastasis, and angiogenesis [14].

One of the most important precancerous stages in gastric cancer (GC), intestinal metaplasia (IM) and dysplasia is the chronic atrophic gastritis (CAG) [30]. Liu et al. reported that the miR-148a was one of the ten hyper-expressed miRNAs as serum exosomes in CAG group same as the chronic non-atrophic gastritis (CNAG) group [30]. They showed that the miR-122 was the most promising biomarker for the molecular detection of CAG. However, we had 25 chronic gastritis samples that were H. pylori-negative, and among them, 13 (52%) and 14 (56%) biopsies had an overexpression of miR-148a and Rock1, respectively. Also, among 25 samples with active chronic gastritis that were H. pylori-positive, 15 (60%) and 14 (56%) biopsies had an overexpression of Rock1 gene. However, similar to the research conducted by Liu et al., we selected the CNAG group as control but may the non-gastritis samples be a better control group. H. pylori infection can lead to the gastritis and gastric atrophy, progressing to the gastric cancer that is less dependent on bacteria than intra-tumor cell dynamics [31]. The matrix metalloproteinases (MMPs) are the active factors to progression of gastric cancer and metastasis associated to the H. pylori infection [31]. The miR-148a can suppress the cancerous cell invasion and migration in stomach by targeting methyltransferase 1 and downregulation of the ROCK1 [32, 33]. However, we found a significant relation between the expression of miR-148a and Rock1 among the H. pylori-positive and –negative patients with the same pathological outcomes. This indicate the important role of the mir-148a on the expression of the Rock1 gene in patients with different H. pylori results.

Conclusions

We found an increased expression of Rock1 and mir-148a in both groups of the present study. However, this data was not statistically significant which may be due to the small sample size. On the other hand, although the miR-148a and Rock1 are the sufficient markers for diagnosis of the possible progression of the chronic gastritis to the gastric cancer, but our patients had not such prognosis. However, we can suggest that this study may be conducted on more samples or in comparison with the non-gastritis participants.

Limitation

The most limitation was the small sample size of the present study for the interpretation of the final results.

Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

MALT-B-cell lymphoma:

Mucosa-associated Lymphoid Tissue B-cell Lymphoma

ncRNAs:

Non-coding RNAs

Mir-148a:

MicroRNA-148a

ECM:

Extracellular Matrix

ROCK:

Rho-Associated Coiled-coil Kinase

DNA:

Deoxyribonucleic Acid

RNA:

Ribonucleic Acid

QRT-PCR:

Quantitative Real-time Polymerase Chain Reaction

GAPDH:

Glyceraldehyde 3-phosphate Dehydrogenase

RUT:

Rapid Urease Test

GC:

Gastric Cancer

CAG:

Chronic Atrophic Gastritis

CNAG:

Chronic Non-atrophic Gastritis

MMPs:

Matrix Metalloproteinases

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Acknowledgements

The present study is part of the Master of Science’ student thesis approved by the Mazandaran University of Medical Sciences, Sari, Iran. This study was completed with the financial support and facilities of the university. Thanks to all members of the Department of Medical Microbiology and Virology of the School of Medicine. Also, we thank the staff of the endoscopy section of the Baghban treatment center for the collection of biopsies.

Funding

This study is a report of a database from an MSc student thesis registered and carried out in Immunogenetics Research Center in Mazandaran University of Medical Sciences, Sari, Iran, with grant No. 3251.

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Authors and Affiliations

  1. Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Ebrahim Gholamhosseinzadeh, Narjes Jafari & Hamid Reza Goli

  2. Department of Medical Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Farah Abad blv, Khazar square, Sari, Mazandaran, Iran

    Ebrahim Gholamhosseinzadeh & Hamid Reza Goli

  3. Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Hossein Ghalehnoei

  4. Gut and Liver Research Center, Non-communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran

    Arash Kazemi Veisari

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  1. Ebrahim Gholamhosseinzadeh
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Contributions

EG contributed to the acquisition of data and drafting of the manuscript. HG contributed to the analysis and interpretation of data. AKV contributed to the collection of biopsies. NJ contributed to the primers design and the molecular testing. HRG contributed to the study concept and design, acquisition of data, analysis, and interpretation of data, reviewed and approved the final article. Also, all authors reviewed and approved the final article.

Corresponding author

Correspondence to Hamid Reza Goli.

Ethics declarations

Ethical approval statement and consent of participants

First, a printed informed consent form was provided by the patients with gastric inflammation. The clinical samples of patients were taken by a qualified gastroenterologist in an endoscopy center affiliated with the Mazandaran University of Medical Sciences. This study was done according to the Declaration of Helsinki, and the categorizing data of patients was kept secret. Moreover, this research was approved by the Iran National Committee for Ethics in Biomedical Research with the national ethical code IR.MAZUMS.REC.1397.382.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Gholamhosseinzadeh, E., Ghalehnoei, H., Kazemi Veisari, A. et al. Evaluation of the Rock1 and microRNA-148a expression in biopsies collected from patients with Helicobacter pylori induced gastritis. BMC Gastroenterol 24, 251 (2024). https://doi.org/10.1186/s12876-024-03347-z

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BMC Gastroenterology

ISSN: 1471-230X

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