| Abstract|| |
Objective: Postoperative recurrence and metastasis of gastric cancer is still a difficult problem in medical field. About 60% of patients with advanced gastric cancer die from peritoneal metastasis, which has become one of the main causes of death of gastric cancer patients. To elucidate the molecular mechanism of peritoneal metastasis of gastric cancer can help us better early diagnosis and improve treatment measures. Methods: This project intends to validate the above hypothesis from three different levels of tissue, cell, and animal models by means of fluorescence quantitative PCR, Western blot, double Luciferase Report Analysis and immunohistochemical detection, and to further explore the molecular mechanism of peritoneal metastasis of gastric cancer. Results: Our previous studies have shown that PARK7 promotes peritoneal metastasis of gastric cancer through PI3K/Akt signaling pathway, but its specific regulatory mechanism remains unclear. Conclusion: Our preliminary study showed that the expression of microRNA-216b in gastric cancer tissues with peritoneal metastasis was significantly lower than that in patients without peritoneal metastasis, while the expression of PARK7 was the opposite.
Keywords: Gastric cancer, miR-216b, PARK7, tumor metastasis
|How to cite this article:|
Zhu GM, Chen SQ, Jiang QG, Cao Y, Guo Y, Ye LQ. MiR-216b inhibits gastric cancer proliferation and migration by targeting PARK7. Indian J Pathol Microbiol 2021;64:52-7
|How to cite this URL:|
Zhu GM, Chen SQ, Jiang QG, Cao Y, Guo Y, Ye LQ. MiR-216b inhibits gastric cancer proliferation and migration by targeting PARK7. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jan 21];64:52-7. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/52/306534
Gastric cancer is one of the most common malignant tumors of digestive tract in the world. According to statistics, there are about 600,000 new cases of male and 330,000 new cases of female every year.,, The incidence of gastric cancer may be higher in developing countries such as China and Japan. However, the main reason why the mortality rate of gastric cancer is still rising and not decreasing is that the recurrence and metastasis of gastric cancer after operation is still a difficult problem in the medical field. Peritoneum is a common metastasis site of advanced gastric cancer, and the sign of peritoneal metastasis has entered the middle and late stages. The 5-year survival rate of patients with advanced gastric cancer is less than 15%., About 60% of patients with advanced gastric cancer die of peritoneal metastasis, and peritoneal metastasis accounts for 50% of the recurrence rate of gastric cancer after operation. It has become one of the main causes of death of patients with gastric cancer.,,
To elucidate the molecular mechanism of peritoneal metastasis of gastric cancer can help us better early diagnosis and improve treatment measures. Therefore, it is particularly important to screen molecular markers related to peritoneal metastasis of gastric cancer and construct gene network regulatory maps. PARK7 protein is a mitogen-dependent oncogene product., It is highly conserved and widely expressed in various tissues and cells of the body. It participates in various pathophysiological activities of cells in the form of homologous dimers, such as regulation of gene transcription, antioxidant stress, anti-apoptotic, molecular chaperone and promotion of cell growth and proliferation.,, Mounting evidences demonstrated that PARK7 played important roles in the development of gastric cancer, PARK7 also called DJ-1, it could mediate the apoptosis of human gastric cancer cells via autophagy signaling pathway, and overexpression of PARK7 was highly associated with the metastasis and poor prognosis of gastric carcinoma through AKT signaling pathway or downregulation of PTEN.,, What's more, PARK7 also highly expressed in prostate, ovarian, breast, thyroid, and lung cancer tissues,, further proved the outstanding of this study.
We clarified the differential expression of PARK7 in gastric cancer and it plays a role through PTEN/PI3K/Akt. Further transfection of SGC7901 gastric cancer cells via PARK7-shRNA eukaryotic expression vector can significantly reduce the expression of PARK7 gene at the level of mRNA and protein. But the underlying mechanism what molecular regulation it is specifically and whether it is regulated by miRNAs during the invasion and metastasis of gastric cancer remained unknown.
MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs with negative regulatory effects composed of 19-25 nucleotide bases. They are small non-coding single-stranded RNAs with high conservativeness, time and tissue specificity and pass through the target genes. Complete or incomplete base pairing of NA, RNA-induced silencing complexes can degrade target genes or inhibit translation, and regulate the expression of target genes at post-transcriptional level. MiRNAs widely exist in eukaryotic organisms and regulate cell proliferation, differentiation, and apoptosis. Specific microRNAs are highly or poorly expressed in different tumors and stages. Protein kinase C is a family of calcium-activated phospholipid-dependent serine/threonine protein kinases in the cytoplasm. It is widely involved in regulating many biological events in life, such as immune mediation, transcriptional regulation, learning and memory, cell growth and components, metabolism and disease. It was well-known that miR-216b was widely expressed in various malignant cancers such as non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, breast cancer, cervical cancer, prostate cancer, pancreatic cancer, and so forth, miR-216b suppresses colorectal cancer proliferation, migration, and invasion by targeting SRPK1, which shed light on how miR-216b functions in CRC pathogenesis, miR-216b was involved in cisplatin resistance in ovarian cancer, which could be regarded as a potential sensitizer in cisplatin chemotherapy. However, whether there are such findings for gastric cancer remains unknown. Only few studies reported that miR-216b was downregulated in human gastric adenocarcinoma and it could repressed the cell proliferation and cell cycle by targeting the oncogene HDAC8. But until now, whether there could be relationship between miR-216b and PARK7 in human gastric cancer or not still remain elusive, and further investigation attracted much more attention in this field.
Based on the above research background and previous work, we propose the hypothesis that microRNA-216b acts on PARK7 to inhibit the invasion and metastasis of gastric cancer. In order to verify the above hypothesis, this project intends to use fluorescent quantitative PCR, Western blot, double luciferase reporter analysis, immunohistochemical detection and other experimental methods to verify the above hypothesis from three different levels of tissue, cell, and animal model. To further inhibit the molecular mechanism of peritoneal metastasis of gastric cancer.
| Materials and Methods|| |
Ten patients with non-metastatic gastric cancer, 10 patients with metastatic gastric cancer (peritoneal metastasis), and 10 patients with non-gastric cancer (control group) were selected, respectively. Tissue specimens were obtained and total RNA was extracted by TRIzol method. The total RNA was retrieved according to the instructions of the reverse transcription kit.
Flow cytometry, cell viability, migratory invasion assays
Fluorescence-activated cell-sorting (FACS) analysis for cell cycle and apoptosis was done 72 hours post-transfection, using nuclear stain DAPI (40,6-diamidino-2-phenylindole) for cell-cycle analysis or Annexin V-FITC/7-AAD Kit (Beckman Coulter, Inc.) for apoptosis analysis, according to the manufacturer's protocol. Cell viability was determined at 24, 48, and 72 hours by using the CellTiter 96 AQueousOne Solution Cell Proliferation Assay Kit (Promega), according to the manufacturer's protocol. An artificial ''wound'' was created on a confluent cell monolayer, and photographs were taken after 24 hours for migration assay. Also, a cytoselect 24-well cell migration assay kit (Cell Biolabs, Inc.) was used for migration assays, according to manufacturer's protocol.
Western blot analysis
Western blot analysis was used to evaluate PARK7 protein expression in the transfected cells. Briefly, the cells were collected and lysed with RIPA buffer for 10 min on ice. Following centrifugation at 8,000 x g for 30 min at 4°C, the supernatant was removed, and the protein concentration was measured by bicinchoninic acid assay. Totally, 50 μg protein was analyzed using 10% SDS-PAGE. Following gel separation, the proteins were transferred into the polyvinylidene difluoride membrane and blocked in 5% milk. Rabbit polyclonal antibody, were used as primary antibodies. The horseradish peroxidase-conjugated goat monoclonal to rabbit immunoglobulin G was used as the secondary antibody. The bound antibodies were detected using Enhanced Chemiluminescence Plus Western Blotting Detection system.
10% neutral formalin was immobilized, dehydrated, paraffin-embedded, and cut into 4-micron thick tissue sections. Goat serum was dripped and sealed for 30 minutes. Antibodies against related proteins were added. The second antibody was labeled with FITC or biotin and stained with ABC method. Negative control group, positive control group, and fluorescent marker control group were set up. IMAGE PRO 5.1 software (Media Cybernetics) was used to analyze the area and optical density of positive staining. Fromowitz and other comprehensive scoring methods were used and slightly improved to divide them into four grades (--++). Under 200-fold microscope, each slice was randomly selected to count the average number of positive cells in 5 visual fields. No positive cells were counted in 0 points, the number of positive cells was less than 25% in 1 point, the number of positive cells was 26%–50% in 2 points, and the number of positive cells was 2 points. The number of cells ranged from 51% to 75% with 3 points and the number of positive cells <75% with 4 points. The expression of slices was light yellow with 1 score, brown with 2 score and brown with 3 score. Grading by the sum of scores: 0 is negative (-), 2, 3 is weak positive (+), 4, 5 is moderate positive (+), 6, 7 is strong positive (++).
Dual Luciferase Reporting Analysis
The luciferase activity of the samples was detected by Promega double Luciferase Report detection kit. After 48 hours of transfection, the medium in the 24-well plate was destroyed and washed twice with PBS. According to the instructions, PLB100 μl was added into each hole and shaken slightly on the shaking table for 15 minutes. The cracking fluid in the collector plate. Relevant reagents will be ready for computer testing. Using the automatic light-emitting detector, the program pre-reading is set to 2 s, the reading value is 10 s, and the dosage of LAR II and Top & Glo Reagent is 100 ul each time. First, the cracking liquid 20 μl is added to the light-emitting board and the bioluminescence detector is put into it. The LAR II and Top & Glo Reagent are added to the light-emitting board, and the program is run to test and read. The fluorescence values were obtained and the data were preserved. The results of fluorescence detection included fluorescein (F) of firefly and fluorescein (R) of sea kidney. The activity multiple of fluorescein was equal to (F/R) sample/(F/R) control.
All quantified data represent an average of at least triplicate samples or as indicated. Error bars represent SD of the mean. Statistical significance was determined by the Student's t test and 2-tailed P values less than 0.05 were considered significant.
| Results|| |
MiR-216b is downregulated in metastatic gastric cancer tissues
To detect the miR-216b expression levels in metastatic gastric cancer tissues, we examined them in 15 paired metastatic gastric cancer tissues and corresponding non-cancerous tissues using RT-qPCR [Figure 1]. The results demonstrated miR-216b was downregulated in the majority of the 15 gastric cancer tissues compared with those in the corresponding non-cancerous tissues and non-metastatic gastric cancer, indicating that the low-level expression of miR-216b may be correlated with gastric metastasis.
|Figure 1: MiR-216b is downregulated in metastatic gastric cancer tissues, while Park7 is upregulated. *P < 0.05 vs. non-cancerous tissues|
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Our preliminary experiments showed that the expression of microRNA-216b and PARK7 was different in gastric cancer cells, and the expression of microRNA-216b in gastric cancer tissues with peritoneal metastasis was significantly lower than that in patients without peritoneal metastasis, while the expression of PARK7 was just the opposite [Figure 1].
MiR-216b overexpression inhibits gastric cancer cell proliferation and migration.
To investigate the function of deregulated miR-216b expression in the gastric cancer cellular process, ectopic expression of miR-216b was achieved in BGC823 and CDH17-NEG cells by transient transfection with miR-216b mimics [Figure 2]a. Cell viability was investigated at the indicated time-points by MTT assay. As indicated in [Figure 2]b, it was demonstrated that ectopic miR-216b expression increased BGC823 cell viability by ~15%, compared with that of the mimics ctrl-transfected cells. Ectopic miR-216b expression had the same effect on CDH17-NEG cell viability. A trans-well assay was performed to determine the roles of miR-216b in gastric cancer cell migration. It was discovered that miR-216b increased the migration in BGC823 and CDH17-NEG cells, respectively [Figure 2]c, compared to that of the mimics ctrl group. These results suggested that miR-216b contributed to G1/S phase transition and cell proliferation.
|Figure 2: MiR-216b overexpression inhibits gastric cancer cell proliferation and migration. Cells were transiently transfected with miR-216b mimics or control and RNA was subsequently isolated for functional studies. (a) Reverse transcription polymerase chain reaction was performed for the analysis of miR-216b expression. U6 snRNA was used as an internal control. (b) Cell viability was measured by MTT assay at various time-points following transfection. (c) Transfected cells were subjected to cell migration assay. Data are from three independent experiments and values are presented as the mean ± standard deviation. *P < 0.05 vs. control group. miR, microRNA; snRNA, small nuclear RNA|
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Inhibition of MiR-216b promotes gastric cancer cell proliferation and migration
To investigate whether miR-216b expression was essential for gastric cancer cell growth, endogenous miR-216b expression was inhibited via transient transfection with an miR-216b inhibitor. The reduction in expression of miR-216b caused by the miR-216b inhibitor was confirmed by RT-qPCR [Figure 3]a. An MTT assay indicated that the inhibition of miR-216b led to a ~50% increase in cell viability [Figure 3]b. Accordingly, the migration in BGC823 and CDH17-NEG cells was also increased due to the inhibition of miR-216b [Figure 3]c. These results demonstrated a significant role for miR-216b in pathogenesis of gastric cancer.
|Figure 3: Inhibition of MiR-216b promotes gastric cancer cell proliferation and migration. Cells were transiently transfected with miR-216b inhibitor or control and RNA was subsequently isolated for functional studies. (a) Reverse transcription quantitative polymerase chain reaction was performed for the analysis of miR-216b expression. U6 snRNA was used as an internal control. (b) Cell viability was measured by MTT assay at various time-points following transfection. (c) Transfected cells were subjected to cell migration assay. Data are from three independent experiments and values are presented as the mean ± standard deviation. *P < 0.05 vs control group|
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Over-expression of MiR-216b inhibits the PI3K/AKT pathway in gastric cancer cells
The PI3K/AKT pathway is associated with cell proliferation and invasion in gastric cancer (11-14). To confirm whether miR-216b affects the PI3K/AKT signaling pathway in gastric cancer, western blot was carried out to analysis the protein expression levels of PI3K/AKT pathway. The results showed that miR-216b over-expression reduced the phosphorylation expression levels of AKT and mTOR, and decreased the protein levels of PARK7 in BGC823 and CDH17-NEG cells, as compared with in the control group [Figure 4]. Therefore, these results indicated that miR-216b inhibits the PI3K/AKT pathway in gastric cancer cells. Our results confirmed that miR-216b is a potential regulator of PI3K/AKT signaling pathway in gastric cancer.
|Figure 4: Over-expression of MiR-216b inhibits the PI3K/AKT pathway in gastric cancer cells. Cells were transiently transfected with miR-216b mimics or control and RNA was subsequently isolated for functional studies. WB was performed to show the protein expression levels of PI3K/AKT pathway|
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MiR-216b directly regulates PARK7 expression by targeting their 3'UTR
Further, we predicted the downstream target genes of microRNA-216b by the online prediction software MicroWalk, which showed a higher predictive value of PARK7 (P = 0.0009). MicroRNA-216b could bind to its 3'UTR region, resulting in a decrease in its synthesis [Figure 5]a.
|Figure 5: MiR-216b directly regulates PARK7 expression by targeting their 3'UTR. (a) Cells were transfected with miR-216b mimics or control and harvested for RNA isolation to analyze the effect of miR-96 on Park7 mRNA expression levels by reverse transcription quantitative polymerase chain reaction. β-actin was used as an internal control. (b) Alignments between miR-216b and the binding sites in the sequences at the 3'UTR. A mutation within the binding sites was generated. The asterisks represent the mutated nucleotides. (c) Cells were co-transfected with miR-216b and the WT or mutant 3'UTR and subjected to luciferase reporter assay for the analysis of the effect of miR-216b on the intensity controlled by the 3'UTR. Data were from three independent experiments and values are expressed as the mean ± standard deviation. *P < 0.05 vs. control|
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To investigate the direct regulatory roles of miR-216b on PARK7, the 3'UTR-containing miR-216b binding sites [Figure 5]b were cloned downstream of the luciferase reporter gene. The cells were subsequently co-transfected with miR-216b and the cloned luciferase reporter. As indicated in [Figure 5]b, it was observed that miR-216b significantly inhibited luciferase intensity of the 3'UTR of PARK7. To further confirm that these binding sites mediated the inhibitory function of miR-216b, mutations within the binding sites were generated. It was demonstrated that miR-216b did not influence the fluorescence intensity of PARK7 containing the mutant 3'UTR [Figure 5]c. These results suggested that PARK7 could be direct target genes of miR-216b and were negatively regulated by miR-216b.
| Discussion|| |
Since the prognosis of primary signet ring cell carcinoma (SRCC) is extremely poor, early diagnosis and aggressive treatment strategy are necessary. In recent years, with the improvement of people's living standards, changes in lifestyle and dietary structure, and people's attention to physical health and physical examination, gastric cancer can be detected earlier and diagnosed earlier. With the in-depth study in recent years, many markers of peritoneal metastasis of gastric cancer have been found, and some of them have been used in clinical diagnosis and treatment, but the detection rate and positive rate are not ideal. The peritoneal metastasis of gastric cancer is a complex process consisting of a series of individual events, which are regulated by many factors, such as different types of tumor metastasis-related genes acting on various target molecules under different conditions, and playing different roles through different signal transduction pathways.
In this study, we revealed that miR-216b was downregulated in gastric cancer tissues, compared to expression levels in adjacent normal tissues. Furthermore, knockdown of miR-216b promoted gastric cancer cell viability and migration, while overexpression of miR-216b suppressed cell proliferation, which indicated that miR-216b functioned as a tumor suppressive miRNA in gastric cancer.
Early studies on PARK7 mainly focused on the relationship between PARK7 and Parkinson's disease. Recently, more and more data show that PARK7 is closely related to cancer. When PARK7 gene was cloned and identified, it was found that PARK7 could promote the transformation and tumorigenicity of NIH3T3 cells. Subsequent studies found that PARK7 expression in prostate, ovarian, breast, thyroid and lung cancer tissues or cells was significantly higher than that in adjacent peripheral tissues or positive cells. These studies suggest that PARK7 may play an important role in tumor progression.,, At the same time, with the further study of PARK7, the abnormal expression of PARK7 in tumor invasion and metastasis has attracted more and more attention. In the study of non-small cell lung cancer, Kim et al. found that PARK7 was highly expressed in cancer tissues and correlated with short-term recurrence time. Subsequently, Yuen et al. found that the expression of PARK7 in the cytoplasm of esophageal squamous cell carcinoma and lymph node metastasis was higher than that of non-cancer epithelium, and the level of PARK7 in tumor cells with distant metastasis was significantly higher than that in primary or low metastasis tumors. In addition, in the study of hepatocellular carcinoma, scholars also found that PARK7 was highly expressed in hepatocellular carcinoma tissues, which was positively correlated with whether the tumor had capsule or not and whether there was portal vein tumor thrombus., In addition, Fang et al. also found that high expression of PARK7 could promote the invasion and migration of SWO-38 glioma cells, while low expression of PARK7 inhibited the invasion of SWO-38 cells. Migration. These studies suggest that the expression of PARK7 may play an important role in the invasion and metastasis of tumors.
The literature shows that the expression level of microRNA-216b in nasopharyngeal carcinoma is significantly reduced, and this decrease is closely related to the expression of KRAS gene. In addition, in the screening of biomarkers for gastric cancer, the expression of microRNA-216b also showed a similar trend with that in nasopharyngeal carcinoma, suggesting that microRNA-216b may be a potential target inhibitor of gastric cancer.,,
In conclusion, knockdown of miR-216b could promote cell proliferation and migration in gastric cancer cells by targeting PARK7 through AKT signaling pathway in vitro and in vivo, which could facilitate the metastasis of gastric cancer. Inhibition of PARK7 expression could reverse miR-96-knockdown-induced cell proliferation and migration. These findings may provide important information for further experimental and clinical investigation on the mechanism of gastric cancer and present potentially diagnostic or therapeutic strategies for gastric cancer.
Ethics, consent, and permissions
Ethical approval was provided by the Medical Ethics Committee of the First Affiliated Hospital of Nanchang University.
Consent to publish
All authors have consented to publish this research.
Financial support and sponsorship
Jiangxi provincial department of education science and technology research project, No.: 170058
Conflicts of interest
There are no conflicts of interest.
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Department of General Surgery, The First Affiliated Hospital of Nanchang University, Yongwai Street, Nanchang 330006
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]