Tumor Suppressor In Gastric Cancer Research Articles

MiR-3178 as a prognostic indicator and tumor suppressor of gastric cancer.

Gastric cancer is a common malignant tumor with an increasing death rate. MicroRNA can serve as a promising biomarker for the progression and prognosis of various cancers. The clinical significance and biological function of miR-3178 in gastric cancer was assessed in this study. A total of 117 paired tissues were collected from gastric cancer patients. Quantitative real-time polymerase chain reaction was used to detect the expression of miR-3178 in gastric cancer tissues and cells. The association between miR-3178 expression and the clinicopathological features of patients were analyzed by χ2 test. Kaplan-Meier analysis and Cox regression were employed to investigate the prognostic value of miR-3178. Finally, the effect of miR-3178 on the cellular process of gastric cancer was investigated by CCK-8 and transwell assay. miR-3178 was downregulated in gastric cancer tissues and cells, which showed a significant association with the TNM stage and lymph node metastasis of patients and a poor prognosis. MiR-3178 and TNM stage were considered as two independent prognostic factors for gastric cancer. Furthermore, the downregulation of miR-3178 promoted cell proliferation, migration, and invasion of gastric cancer by regulating Notch1. miR-3178 may be involved in the progression of gastric cancer, which provides new insights into the treatment of gastric cancer.

Circular RNA hsa_circ_0009172 suppresses gastric cancer by regulation of microRNA-485-3p-mediated NTRK3.

Gastric cancer is the third leading cause of cancer-related death worldwide, with relapse and metastasis being major contributors to the mortality. Circular RNAs (circRNAs) have been at the center of several researches and some circRNAs have been indicated to be involved in gastric cancer as sponges. Nevertheless, the mechanism underlying the function of circRNA remains largely unclear. Therefore, this study was conducted with the main objective of screening the associated circRNA in gastric cancer and exploring its mechanism. Expression of hsa_circRNA_0009172 was validated in gastric cancer tissues and cell lines after the correlation between hsa_circRNA_0009172 and prognosis was determined. Moreover, the binding site between miR-485-3p and hsa_circRNA_0009172 or NTRK3 was verified using dual luciferase assay and RNA pull down. Function-gain and -loss experiments were performed for the purpose of detecting the effect of hsa_circRNA_0009172 in vivo and in vitro as well as its mechanism with microRNA (miRNA)-485-3p and NTRK3 in gastric cancer. The hsa_circRNA_0009172 expression was downregulated in gastric cancer tissues and cell lines, indicating a positive association with patient prognosis. Functionally, hsa_circ_0009172 overexpression inhibited proliferative, invasive and migrative potential of gastric cancer cells as well as epithelial-mesenchymal transition (EMT)-related proteins by sponging miR-485-3p to inhibit NTRK3, while miR-485-3p overexpression could reverse the inhibitory effect of hsa_circ_0009172 on gastric cancer. Furthermore, either up-regulation of hsa_circ_0009172 or down-regulation of miR-485-3p led to the suppression of xenograft tumor growth in nude mice. In conclusion, hsa_circ_0009172 serves as a tumor suppressor in gastric cancer by targeting miR-485-3p/NTRK3 axis.

MiRNA-4537 functions as a tumor suppressor in gastric cancer and increases the radiosensitivity of gastric cancer cells

ABSTRACT Radiotherapy is a common method to treat gastric cancer (GC). However, the clinical outcomes of GC radiotherapy face challenges, and the mechanisms of GC radioresistance remain unclear. Our study aimed to investigate the role and mechanism of miR-4537 in the radiation sensitivity of GC cells. Cell viability was determined by Cell Counting Kit-8. The proliferation of HGC27 and KATO III cells was measured using a colony formation assay. Flow cytometry was performed to examine the changes in cell apoptosis. Western blotting was conducted to detect the expression of zinc finger protein 587 (ZNF587) protein in HGC27 and KATO III cells. To confirm the relationship between miR-4537 and ZNF587, a luciferase reporter assay was performed. MiR-4537 was downregulated in GC tumors and cells and suppressed cell proliferation, while promoting cell apoptosis in GC. Importantly, we found that miR-4537 reduced the radioresistance of GC cells. In addition, we also confirmed that miR-4537 expression is negatively correlated with ZNF587 expression in GC tissues. MiR-4537 bound to ZNF587 and suppressed the expression level of ZNF587. Overexpression of ZNF587 partially counteracted the effects of miR-4537 on cell proliferation and apoptosis. In conclusion, in GC cells, miR-4537 inhibited the ability of cell proliferation, but on the contrary, it promoted the ability of cell apoptosis and improved radiosensitivity of the cells.

Long noncoding RNA LINC00982 upregulates CTSF expression to inhibit gastric cancer progression via the transcription factor HEY1.

Upregulating the expression of long noncoding RNA LINC00982 controlled cell proliferation in gastric cancer, but the regulatory molecular mechanisms are yet to be expounded. We here aimed to elaborate how LINC00982 regulated the malignancy of gastric cancer cells. RT-qPCR and Western blot analysis were used to detect the expression of LINC00982 and cathepsin F (CTSF) in gastric cancer tissues and cells. Modulatory effect of LINC00982 on gastric cancer cells was assessed by CCK-8, colony formation, Transwell migration, and invasion assays. The relationship between LINC00982, YRPW motif 1 (HEY1), and CTSF was examined by RNA-binding protein immunoprecipitation, luciferase assay, and chromatin immunoprecipitation, and their interaction in the regulation of gastric cancer cellular functions was analyzed by performing gain-of-function and rescue assays. The nude mouse model of tumor formation was developed to examine the effects of LINC00982 on tumorigenesis. LINC00982 was lowly expressed in gastric cancer tissues, whereas its overexpression impaired the proliferative, migratory, and invasive properties of gastric cancer cells. Furthermore, LINC00982 could bind to transcription factor HEY1 and inhibited its expression. Through blocking the binding of HEY1 to CTSF promoter, LINC00982 promoted the expression of CTSF. Overexpression of HEY1 or inhibition of CTSF could reverse the antitumor effects of LINC00982 on gastric cancer, which were further demonstrated in vivo. All these taken together, LINC00982 acted as a tumor suppressor in gastric cancer, which is therefore suggested to be a potential antitumor target for gastric cancer.NEW & NOTEWORTHY We identified LINC00982 as a promising antitumor target for the treatment of patients with gastric cancer. We also determined a regulatory network involved in the pathophysiology of gastric cancer wherein LINC00982 could bind to HEY1 to impair its binding to cathepsin F (CTSF) promoter and hence promote CTSF expression, which aids in better understanding of molecular mechanisms related to gastric tumorigenesis.

SIK2 represses AKT/GSK3β/β-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases.

Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3β/β-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3β/β-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.

Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit

BackgroundEmerging evidence has shown that circular RNAs (circRNAs) play a crucial regulatory role in the occurrence and development of cancer. Exploring the roles and mechanisms of circRNAs in tumorigenesis and progression may help to identify new diagnostic markers and therapeutic targets. In the present study, we investigated the role and regulatory mechanism of hsa_circ_0004872 in gastric cancer (GC).MethodsqRT-PCR was used to determine the expression of hsa_circ_0004872 in GC tissues and cells. EdU, CCK-8, transwell and scratch wound healing assays were used to assess the role of hsa_circ_0004872 in GC cell proliferation, invasion and migration, respectively. Subcutaneous and tail vein tumor injections in nude mice were used to assess the role of hsa_circ_0004872 in vivo. RIP assay, biotin-coupled probe pull-down assay, FISH and luciferase reporter assay were performed to confirm the relationship between hsa_circ_0004872 and the identified miRNA. ChIP assay, luciferase reporter assay and western blot were used to determine the direct binding of Smad4 to the promoter of the ADAR1 gene.ResultsIn this study, we found that hsa_circ_0004872 was dramatically downregulated in GC tissues compared with adjacent noncancerous tissues. The expression level of hsa_circ_0004872 was associated with tumor size and local lymph node metastasis. Enforced expression of hsa_circ_0004872 inhibited the proliferation, invasion and migration of GC cells, whereas knockdown of hsa_circ_0004872 had the opposite effects. Nude mice experiments showed that ectopic expression of hsa_circ_0004872 dramatically inhibited tumor growth and metastasis in vivo. Moreover, we demonstrated that hsa_circ_0004872 acted as a “molecular sponge” for miR-224 to upregulate the expression of the miR-224 downstream targets p21 and Smad4. Importantly, we found that the RNA-editing enzyme ADAR1 inhibited hsa_circ_0004872 expression and further led to the upregulation of miR-224. Smad4, the downstream target of miR-224, could further affect hsa_circ_0004872 levels by directly binding to the promoter region of ADAR1 to inhibit ADAR1 expression.ConclusionsOur findings showed that hsa_circ_0004872 acted as a tumor suppressor in GC by forming a negative regulatory loop consisting of hsa_circ_0004872/miR-224/Smad4/ADAR1. Thus, hsa_circ_0004872 may serve as a potential biomarker and therapeutic target for GC.

POC1A acts as a promising prognostic biomarker associated with high tumor immune cell infiltration in gastric cancer.

The effect of POC1 centriolar protein A (POC1A) on gastric cancer (GC) has not been clearly defined. In this study, POC1A expression and clinical information in patients with GC were analyzed. Multiple databases were used to investigate the genes that were co-expressed with POC1A and genes whose changes co-occurred with genetic alternations of POC1A. Moreover, the TISIDB and TIMER databases were used to analyze immune infiltration. The GSE54129 GC dataset and LASSO regression model (tumor vs. normal) were employed, and 6 significant differentially expressed genes (LAMP5, CEBPB, ARMC9, PAOX, VMP1, POC1A) were identified. POC1A was selected for its high expression in adjacent tissues, which was confirmed with IHC. High POC1A expression was related to better overall and recurrence-free survival. GO and KEGG analyses demonstrated that POC1A may regulate the cell cycle, DNA replication and cell growth. Furthermore, POC1A was found to be correlated with immune infiltration levels in GC according to the TISIDB and TIMER databases. These findings indicate that POC1A acts as a tumor suppressor in GC by regulating the cell cycle and cell growth. In addition, POC1A preferentially regulates the immune infiltration of GC via several immune genes. However, the specific mechanism requires further study.

LINC01436 Promotes the Progression of Gastric Cancer via Regulating miR-513a-5p/APE1 Axis.

BackgroundGastric cancer (GC) is one of the deadliest cancer worldwide. Multiple long non-coding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumor suppressors in GC. In this study, we aimed to probe into the effect of LINC01436 on GC progression.MethodsLINC01436 and miR-513a-5p expressions in GC tissue samples were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used to detect the expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) expression. Human GC cell lines AGS and BGC-823 were employed to investigate the function and mechanism of LINC01436 in GC. Cell counting kit-8 (CCK-8) assay was used to assess the effect of LINC01436 on proliferation. Flow cytometry was utilized to explore the effect of LINC01436 on apoptosis, and Transwell assay was conducted to detect the effect of LINC01436 on the migration and invasion. Colony formation assay was performed to evaluate the effect of LINC01436 on radioresistance of GC cells. Furthermore, luciferase reporter assay and RNA immunoprecipitation assay were conducted to confirm the binding relationship between miR-513a-5p and LINC01436. Additionally, Western blot was used to study the regulatory function of LINC01436 and miR-513a-5p on APE1.ResultsLINC01436 expression of GC clinical samples was remarkably increased and LINC01436 was correlated with unfavorable pathological indexes. LINC01436 high expression was associated with shorter overall survival time. Its overexpression observably promoted the proliferation, metastasis and radioresistance of GC cells, and its knockdown suppressed the malignant phenotypes of GC cells. LINC01436 overexpression markedly reduced the miR-513a-5p expression via sponging it and enhanced the APE1 expression. MiR-513a-5p overexpression or APE1 knockdown reversed the effects of LINC01436 on GC cells.ConclusionLINC01436 is a molecular sponge of tumor suppressor miR-513a-5p, which indirectly enhances the APE1 expression and functions as the oncogenic lncRNA in GC.

ERRATUM.

It has been demonstrated that microRNAs (miRNAs) act as oncogenes or tumor suppressors in a variety of cancers. Our previous work suggested that miR-10a/b functioned as a tumor suppressor in gastric cancer, and miR-10b was also reported to be significantly downregulated in advanced stage cervical cancer tissues. However, the aberrant expression of miR-10b in cervical cancer and its possible role in cervical carcinogenesis was largely unknown. In this study, we investigated the expression of miR-10b in cervical cancer tissues, carcinoma in situ tissues, mild dysplasia, moderate dysplasia, severe dysplasia tissues, and normal controls. We found that miR-10b was significantly downregulated during cervical cancer progression, and the lower level of miR-10b in cervical cancer was significantly associated with a more aggressive tumor phenotype. Moreover, overexpression of miR-10b in cervical cancer cells could inhibit the cell proliferation and invasion, and the further mechanism study suggested that its role was possibly through directly targeting HOXA1. These results suggested that the downregulation of miR-10b and the resulting elevated HOXA1 level in cervical cancer tissues might play critical roles in cervical cancer progression.

THAP11 Functions as a Tumor Suppressor in Gastric Cancer through Regulating c-Myc Signaling Pathways

We aim to investigate the role of THAP11 (thanatos-associated protein11) in gastric cancer and its regulation mechanisms. THAP11 expression was analyzed in 51 pairs of GC tissues and the corresponding paracancerous tissues by qRT-PCR and Western blot. After THAP11 was overexpressed or knocked-down, cell proliferation, cell cycle, and apoptosis were detected in MKN-45 cells. We found that THAP11 was significantly downregulated in GC tissues and GC cell lines. Functionally, THAP11 overexpression markedly inhibited cell growth, induced G1/G0 cell-cycle arrest, and promoted cell apoptosis of MKN-45 cells, while silencing of THAP11 led to increased cell growth, increased DNA synthesis, and inhibited apoptosis. In addition, THAP11 negatively regulated the expression of c-Myc, decreased cyclinD1 protein, and increased p27 and p21 protein levels. We also found cell growth suppression induced by THAP11 was rescued by c-Myc overexpression, further confirming that THAP11 suppresses gastric cancer cell growth via the c-Myc pathway. THAP11 acts as a cell growth suppressor and exerts its role possibly through negatively regulating c-Myc pathway in gastric cancer.

Epigenetic silencing of long non-coding RNA BM742401 in multiple myeloma: impact on prognosis and myeloma dissemination

BackgroundLong non-coding RNA (lncRNA) BM742401 is a tumor suppressor in gastric cancer and chronic lymphocytic leukemia. As the promoter and coding region of BM742401 are fully embedded in a CpG island, we hypothesized that BM742401 is a tumor suppressor lncRNA epigenetically silenced by promoter DNA methylation in multiple myeloma.MethodsMethylation-specific PCR and quantitative bisulfite pyrosequencing were performed to detect the methylation of BM742401 in normal plasma cells, myeloma cell lines and primary myeloma samples. The expression of BM742401 was measured by qRT-PCR. The function of BM742401 in multiple myeloma cells was analyzed by lentivirus transduction followed by migration assay.ResultsBM742401 methylation was detected in 10 (66.7%) myeloma cell lines but not normal plasma cells, and inversely correlated with expression of BM742401. In primary samples, BM742401 methylation was detected in 3 (12.5%) monoclonal gammopathy of undetermined significance, 9 (15.8%) myeloma at diagnosis and 8 (17.0%) myeloma at relapse/progression. Moreover, BM742401 methylation at diagnosis was associated with inferior overall survival (median OS: 25 vs. 39 months; P = 0.0496). In myeloma cell line JJN-3, stable overexpression of BM742401 by lentivirus transduction resulted in reduced cell migration (P = 0.0001) but not impacting cell death or proliferation.ConclusionsThis is the first report of tumor-specific methylation-mediated silencing of BM742401 in myeloma, which is likely an early event in myelomagenesis with adverse impact on overall survival. Moreover, BM742401 is a tumor suppressor lncRNA by inhibiting myeloma cell migration, hence implicated in myeloma plasma cell homing, metastasis and disease progression.

MiR-502-5p affects gastric cancer progression by targeting PD-L1

BackgroundStudies have shown that miR-502-5p functions as a tumor suppressor and is associated with tumor growth and metastasis. This study intends to uncover the potential mechanism of miR-502-5p functioning as a tumor suppressor in gastric cancer.MethodsExpression levels of miR-502-5p and PD-L1 were measured by using qRT-PCR. Cell proliferation abilities were examined by EDU incorporation assay. Cell migration, invasion and cell cycle analysis of cells were determined by transwell assay, transwell-matrigel assay and flow cytometry, respectively. The relationship between miR-502-5p expression and the overall survival of xenograft tumor mice was statistically analyzed. Bioinformatics analysis and luciferase reporter assays were applied to analyze the relationship between miR-502-5p and CD40, STAT3 or PD-L1. Expressions of CD40, STAT3 and PD-L1 at protein level were detected by western blot.ResultsThe results showed that miR-502-5p was significantly downregulated in gastric cancer tumor tissues compared with adjacent normal tissues. Overexpression of miR-502-5p significantly attenuated the proliferation, migration/invasion and induced the G1 phase arrest of gastric cancer cells. Consistently, miR-502-5p suppressed tumor growth and metastasis in vivo. Mechanically, we demonstrated that miR-502-5p had inhibited the malignant behaviour of gastric cancer by down-regulating PD-L1 expression at transcriptional level and post-transcriptional levels.ConclusionsThese findings suggest that miR-502-5p acts as a tumor suppressor in gastric cancer (GC). MiR-502-5p/PD-L1 may be a novel therapeutic target in GC treatment.

Abstract 4786: Potential role of p53-Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric and esophageal cancers Potential role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric, esophageal and breast cancers

Abstract [Background] Despite its early diagnosis and improved intensive treatments, gastric cancer (GC) remains the third leading cause of death throughout the world. In particular among upper gastrointestinal cancers, it is most prevalent in eastern Asia including Japan, Korea, and China. p53 is a transcription factor that activates the expression of various downstream genes in response to DNA damage. The central functions of this protein in tumor suppression are cell cycle arrest, apoptosis, DNA repair, and anti-angiogenesis. Mitochondria-eating protein (Mieap) is a p53-target that plays an important role in mitochondrial quality control (MQC). Mieap has been reported to have a critical role in tumor suppression in colorectal and breast cancers. Here, we investigated its role as a tumor suppressor in gastric cancer (GC) and esophageal cancer (EC). [Materials and Methods] To investigate the role of Mieap, Mieap-expressing adenovirus (Ad-Mieap) was used to infect GC cells, which were then analyzed by FACS, western blot, and caspase assays. Next, we evaluated the potential disruption of the p53-Mieap-regulated MQC pathway in vivo. Methylation-specific PCR (MPS) for Mieap, NIX, and BNIP3 promoters and p53 mutation detection were performed using genomic DNA from cryopreserved surgical specimens. [Results] Exogenous Mieap in GC cells induced the formation of vacuole-like structures (called MIVs, Mieap-induced vacuoles) and caspase-dependent apoptosis, with the activation of both caspase-3 and caspase-9. In particular, NIX, a mitochondrial apoptotic factor was involved in this phenotype. Of 47 GC patient samples, promoter methylation of Mieap, BNIP3, and NIX was identified in two (4.3%), 29 (61.7%), and zero (0%) specimens, respectively. In total, 33 GC patient samples (70.2%) revealed inactivation of the p53/Mieap-regulated MQC pathway. Interestingly, we found that the BNIP3 promoter in the normal epithelium was highly methylated in 18 of 47 GC cases (38.3%). In EC patients, this MQC pathway was inactivated in ten of 12 patients (83.3%). [Conclusion] These results indicate that p53/Mieap-regulated MQC has a critical role in not only breast cancer but also gastrointestinal cancer suppression, possibly in part through the mitochondrial apoptotic pathway. Citation Format: Manabu Futamura, Hitoya Sano, Siqin Gaowa, Akira Nakakami, Kazuhiro Yoshida, Hirofumi Arakawa. Potential role of p53-Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric and esophageal cancers Potential role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric, esophageal and breast cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4786.

Functional roles of E3 ubiquitin ligases in gastric cancer.

To date, >650 E3 ubiquitin ligases have been described in humans, including >600 really interesting new genes (RINGs), 28 homologous to E6-associated protein C-terminus (HECTs) and several RING-in-between-RINGs. They are considered key regulators and therapeutic targets of many types of human cancers, including gastric cancer (GC). Among them, some RING and HECT E3 ligases are closely related to the proliferation, infiltration and prognosis of GC. During the past few years, abnormal expressions and functions of many E3 ligases have been identified in GC. However, the functional roles of E3 ligases in GC have not been fully elucidated. The present article focuses on the functional roles of E3 ligases related to the proteasome in GC. In this comprehensive review, the latest research progress on E3 ligases involved in GC and elaborate their structure, classification, functional roles and therapeutic value in GC was summarized. Finally, 30 E3 ligases that serve essential roles in regulating the development of GC were described. Some of these ligases may serve as oncogenes or tumor suppressors in GC, whereas the pathological mechanism of others needs further study; for example, constitutive photomorphogenic 1. In conclusion, the present review demonstrated that E3 ligases are crucial tumor regulatory factors and potential therapeutic targets in GC. Therefore, more studies should focus on the therapeutic targeting of E3 ligases in GC.

M6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling

BackgroundBATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive.MethodsWe obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo.ResultsBATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC.ConclusionsCollectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

Background3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies.MethodsWestern blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays.ResultsBDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of AktSer473 and mTORSer2448.ConclusionsOur study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.

HIP1R acts as a tumor suppressor in gastric cancer by promoting cancer cell apoptosis and inhibiting migration and invasion through modulating Akt.

BackgroundHuntingtin‐interacting protein 1‐related (HIP1R) is a multi‐domain gene that exerts many cellular functions including altering T cell–mediated cytotoxicity and controlling intracellular trafficking. However, its clinical significance and function in gastric cancer (GC) have not been described.MethodsThe expression levels of HIP1R were tested by the transcriptional and translational expression analysis and immunohistochemistry (IHC) in matched adjacent non‐tumorous vs tumor tissue specimens. The biological function of HIP1R on apoptosis, migration, and proliferation was evaluated by flow cytometry, Transwell, Cell Counting Kit‐8 (CCK‐8) assays, colony formation assays, and EdU labeling assays, respectively.ResultsWe found downregulated HIP1R in GC compared with adjacent non‐tumorous tissue, and HIP1R expression associated with N classification. We further found that the expression of HIP1R could induce apoptosis and inhibit proliferation, migration, invasion of GC cells, possibly through modulating Akt.ConclusionsOur data indicate that HIP1R may act as a potential diagnostic biomarker and a tumor suppressor gene in GC, potentially representing a novel therapeutic target for future GC treatment.

Low expression of CDK12 in gastric cancer is correlated with advanced stage and poor outcome

BackgroundCyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family, modulating multiple cellular functions including DNA damage response (DDR), development and cellular differentiation, transcription, mRNA processing, splicing and pre-mRNA processing. CDK12 has been reported as both tumor suppressor and oncogene in various kinds of tumor. The function of CDK12 in gastric cancer (GC) remains unclear. Methods/ResultsCDK12 mRNA expression was decreased in GC compared with non-tumor tissue based on GEO database. Also, low mRNA expression of CDK12 was detected in GC cell lines by qPCR. Similarly, CDK12 protein expression was also reduced in GC tissues compared with adjacent non-tumor tissues in 177 GC patients as shown by immunohistochemistry. Low expression of CDK12 was associated with organ metastasis, poorly differentiated adenocarcinoma and advanced stage. Consistent with human protein atlas database analysis, Low expression of CDK12 was correlated with worse overall survival (P < 0.001). Multivariate Cox regression indicated that low expression of CDK12 was an independent prognostic factor for GC patients (P < 0.001). Finally, a gene set enrichment analysis was performed to detect underlying internal mechanisms and biological processes. ConclusionsCDK12 is down-regulated in GC and its expression is negatively correlated with advanced stage, poorly differentiated adenocarcinoma and poor outcomes. Our findings suggest that CDK12 may be a potential tumor suppressor in GC.

Circular RNA_LARP4 inhibits cell migration and invasion of prostate cancer by targeting FOXO3A.

The importance of circular RNAs in malignant tumors causes more attention in researchers. Circular RNA_LARP4 is identified as a tumor suppressor in gastric cancer, but the role of circular RNA_LARP4 in prostate cancer (PCa) remains unclear. Our work aims to uncover whether and how circular RNA_LARP4 functions in the PCa development. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to determine the level of circular RNA_LARP4 in PCa tissues and cell lines. The patients' prognosis was analyzed. Circular RNA_LARP4 lentivirus was constructed for transfection of PCa cells. Cell migrated and invaded ability was detected through wound healing assay and transwell assay. Western blot assay was performed to analyze the protein level of FOXO3A. The low circular RNA_LARP4 expression was associated with poor prognosis of PCa patients. The circular RNA_LARP4 was lowly expressed in PCa tissues compared with adjacent samples. The expression of circular RNA_LARP4 was downregulated in PCa cell lines. The cell migrated and invaded ability of PCa cells was inhibited after circular RNA_LARP4 was overexpressed. Furthermore, FOXO3A expression was increased via the overexpression of circular RNA_LARP4. Circular RNA_LARP4 could suppress cell migration and invasion of PCa by upregulating FOXO3A.

LINC00619 restricts gastric cancer progression by preventing microRNA-224-5p-mediated inhibition of OPCML

Several long intergenic noncoding RNAs (lincRNAs) have been linked to carcinogenesis; however, little is known about the role of LINC00619 in gastric cancer (GC). LINC00619 was identified among differentially expressed lncRNAs linked to gastric cancer based on microarray analysis and its relationships with miR-224-5p and opioid binding protein/cell adhesion molecule-like gene (OPCML) were investigated. LINC00619, miR-224-5p, and OPCML expression were measured in GC tissues and cells. Ectopic expression and depletion experiments were conducted to assess the effects of LINC00619, miR-224-5p and OPCML on cell proliferation, invasion, migration and apoptosis as well as their effects on the expression of apoptosis- and metastasis-related genes (Bcl-2, Bax, MMP-2 and MMP-9). Tumorigenicity in the nude mice was also examined. Gastric cancer was characterized by downregulation of LINC00619 and OPCML and upregulation of miR-224-5p. Additionally, we found that miR-224-5p could interact with both LINC00619 and OPCML. Upregulation of LINC00619, which binds to miR-224-5p, led to decreased miR-224-5p expression while increasing the expression of OPCML, a target gene of miR-224-5p. Overexpression of LINC00619 or OPCML or downregulation of miR-224-5p suppressed cell proliferation, invasion, migration and tumorigenicity while promoting apoptosis in GC. Our results indicated that LINC00619 functions as a tumor suppressor in GC by impairing miR-224-5p-mediated inhibition of OPCML.