Signaling Pathway In Gastric Cancer Research Articles

ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer.

Proliferation is a critical characteristic of the progression of gastric cancer (GC). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), the orphan receptor tyrosine kinase-like receptor, exhibits effects on tumor growth due to its abnormal expression in cancer. The goal of our study was to assess the potential regulatory role exerted by the ROR2 on GC cells. Through previous bioinformatics analysis, we discovered an association between ROR2 and the G2/M phase of the GC cell cycle. However, little is known about the link between ROR2 and the G2/M phase cell cycle in GC. Here, the findings of our study indicate that ROR2, after transcribed expression by Twist1, activates the PI3K/AKT/mTOR/S6K signal transduction pathway, thus leading to the acceleration of the G2/M phase and subsequent promotion of cell proliferation in GC. Furthermore, the functional link among ROR2, Twist1, and G2/M phase of cell cycle was also confirmed in mouse xenograft tissues and human tissues. ROR2 expression was correlated with Twist expression and lower survival in vivo. Notably, our suggestion is that focusing on ROR2 as a potential therapeutic approach could show potential for the management of GC.

Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review

Hepatocyte growth factor (HGF) and its receptor, c-Met, play important roles in the occurrence, development, and treatment of gastric cancer (GC). This review explored the function of the HGF/c-Met signaling pathway in GC and its potential targeted therapeutic mechanisms. As one of the most common malignant tumors worldwide, GC has a complex pathogenesis and limited therapeutic options. Therefore, a thorough understanding of the molecular mechanism of GC is very important for the development of new therapeutic methods. The HGF/c-Met signaling pathway plays an important role in the proliferation, migration, and invasion of GC cells and has become a new therapeutic target. This review summarizes the current research progress on the role of HGF/c-Met in GC and discusses targeted therapeutic strategies targeting this signaling pathway, providing new ideas and directions for the treatment of GC.

Curcumin Induces Autophagy-mediated Ferroptosis by Targeting the PI3K/AKT/mTOR Signaling Pathway in Gastric Cancer.

As a very common malignancy of the digestive system, the incidence and mortality rates of gastric cancer (GC) are increasing year by year. The critical role of ferroptosis in cancer development has been well-documented. The polyphenol compound curcumin shows prominent anti-tumor effects in multiple cancer types, including GC. However, whether curcumin participates in GC tumorigenesis by regulating ferroptosis remains unknown. Gastric cancer cells AGS and HGC-27 were treated with curcumin (0, 10, and 20 μM). Cell viability and death were evaluated through CCK-8 and LDH release assays. LC3B expression in cells was estimated through immunofluorescence staining. Intracellular ferrous iron (Fe2+), GSH, MDA, and lipid ROS levels were assessed by corresponding assay kits. The cellular levels of autophagy markers (ATG5, ATG7, Beclin 1, and LC3B), ferroptosis markers (ACSL4, SLC7A11, and GPX4), and phosphorylated (p)-PI3K, p-AKT, and p-mTOR were determined through western blotting. Curcumin attenuated cell viability but stimulated cell death in GC cells. Curcumin enhanced autophagy in GC cells, as demonstrated by the increased levels of ATG5, ATG7, Beclin 1, and LC3B. Besides, curcumin upregulated iron, MDA, GSH, and ACSL4 levels while downregulated lipid ROS, SLC7A11, and GPX4 levels, suggesting its stimulation on ferroptosis in GC cells. Curcumin decreased p-PI3K, p-AKT, and p-mTOR levels in cells. Importantly, the ferroptosis inhibitor ferrostatin-1 overturned the impacts of curcumin on GC cell viability, death, and ferroptosis. Curcumin suppresses GC development by inducing autophagy-mediated ferroptosis by inactivating the PI3K/AKT/mTOR signaling.

COMMD10 inhibited DNA damage to promote the progression of gastric cancer

PurposeThe copper metabolism MURR1 domain 10 (COMMD10) plays a role in a variety of tumors. Here, we investigated its role in gastric cancer (GC).MethodsOnline prediction tools, quantitative real-time PCR, western blotting and immunohistochemistry were used to evaluate the expression of COMMD10 in GC. The effect of COMMD10 knockdown was investigated in the GC cell lines and in in vivo xenograft tumor experiments. Western blotting and immunofluorescence were used to explore the relationships between COMMD10 and DNA damage.ResultsThe expression of COMMD10 was upregulated in GC compared to that in para-cancerous tissue and correlated with a higher clinical TNM stage (P = 0.044) and tumor size (P = 0.0366). High COMMD10 expression predicted poor prognosis in GC. Knockdown of COMMD10 resulted in the suppression of cell proliferation, migration, and invasion, accompanied by cell cycle arrest and an elevation in apoptosis rate. Moreover, the protein expression of COMMD10 was decreased in cisplatin-induced DNA-damaged GC cells. Suppression of COMMD10 impeded DNA damage repair, intensified DNA damage, and activated ATM–p53 signaling pathway in GC. Conversely, restoration of COMMD10 levels suppressed DNA damage and activation of the ATM-p53 signaling cascade. Additionally, knockdown of COMMD10 significantly restrained the growth of GC xenograft tumors while inhibiting DNA repair, augmenting DNA damage, and activating the ATM–p53 signaling pathway in xenograft tumor tissue.ConclusionCOMMD10 is involved in DNA damage repair and maintains genomic stability in GC; knockdown of COMMD10 impedes the development of GC by exacerbating DNA damage, suggesting that COMMD10 may be new target for GC therapy.

Wnt signaling in gastric cancer: current progress and future prospects.

Levels of the Wnt pathway components are abnormally altered in gastric cancer cells, leading to malignant cell proliferation, invasion and metastasis, poor prognosis and chemoresistance. Therefore, it is important to understand the mechanism of Wnt signaling pathway in gastric cancer. We systematically reviewed the molecular mechanisms of the Wnt pathway in gastric cancer development; and summarize the progression and the challenges of research on molecular agents of the Wnt pathway.

Research progress of MicroRNA and its signaling pathways in gastric cancer.

Research progress of MicroRNA and its signaling pathways in gastric cancer.

Exosomal circ50547 as a potential marker and promotor of gastric cancer progression via miR-217/HNF1B axis

BackgroundExosomes, one of small extracellular vesicles, play a vital role in cell to cell communication and contribute to the advancement of tumors through their cargo molecules. Exosomal circRNAs have emerged as significant players in various types of tumors. Thus, this study aimed to investigate how exosomal circRNAs are involved in the diagnosis and progression of gastric cancer (GC). MethodsSerum exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis and Western blot. CCK-8, colony formation and transwell assays were conducted to study the function of hsa_circ_0050547 (named as circ50547). qRT-PCR was used to quantify the expression of circ50547 in GC tissues and serum exosomes. Fluorescence in situ hybridization was applied to detect the cellular distribution of circ50547. Stemness and drug-resistance were detected by sphere formation, WB, flow cytometry and half-maximal inhibitory concentration analyses. Bioinformatic analyses, luciferase experiments, qRT-PCR and WB were used to investigate molecular mechanisms. ResultsWe discovered for the first time a new type of GC-derived exosomal circRNA, circ50547. We found that circ50547 is highly expressed in both GC tissues and serum exosomes. Interestingly, we observed that the diagnostic value of exosomal circ50547 is superior to that of serum circ50547. Circ50547 overexpression enhanced the proliferation, migration, invasion, stemness and drug resistance of GC cells, while knockdown of circ50547 showed the opposite effect. Mechanistically, circ50547 acted as a sponge for miR-217 to regulate the expression of HNF1B, which promoted gastric cancer progression. ConclusionExosomal circ50547 may be a promising marker for the diagnosis and prognosis prediction of GC. These findings suggest that it plays an oncogenic role through miR-217/HNF1B signaling pathway in GC.

MyoD1 promotes the transcription of BIK and plays an apoptosis-promoting role in the development of gastric cancer

ABSTRACT Myogenic differentiation (MyoD) 1, which is known as a pivotal transcription factor during myogenesis, has been proven dysregulated in several cancers. However, litter is known about the precise role and downstream genes of MyoD1 in gastric cancer (GC) cells. Here, we report that MyoD1 is lowly expressed in primary GC tissues and cells. In our experiments, overexpression of MyoD1 inhibited cell proliferation. Downstream genes of MyoD1 regulation were investigated using RNA-Seq. As a result, 138 up-regulated genes and 20 down-regulated genes and 27 up-regulated lncRNAs and 20 down-regulated lncRNAs were identified in MyoD1 overexpressed MKN-45 cells, which participated in epithelial cell signaling in Helicobacter pylori infection, glycosaminoglycan biosynthesis (keratan sulfate), notch signaling pathway, and others. Among these genes, BIK was directly regulated by MyoD1 in GC cells and inhibited cancer cell proliferation. The BIK knockdown rescued the effects of MyoD1 overexpression on GC cells. In conclusion, MyoD1 inhibited cell proliferation via 158 genes and 47 lncRNAs downstream directly or indirectly that participated in multiple signaling pathways in GC, and among these, MyoD1 promotes BIK transcription by binding to its promoter, then promotes BIK-Bcl2-caspase 3 axis and regulates GC cell apoptosis.

Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer.

Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-PI3K/AKT/mTOR-and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.

SCAMP1 silencing inhibits proliferation by attenuating multiple pro-survival signaling pathways in gastric cancer.

Secretory carrier-associated membrane protein 1 (SCAMP1) is the most universally expressed member of the SCAMP family, and its ability to facilitate endocytosis was demonstrated approximately two decades ago. Nevertheless, its roles in cancer biology are largely unknown, although its expression is significantly increased in most cancer types. Herein, we examined the expression of SCAMP1 in gastric cancer (GC) tissues and found that it was aberrantly increased and positively correlated with tumor size and lymph node metastasis. More importantly, increased SCAMP1 expression was associated with poor prognosis in patients with GC. Functional experiments demonstrated that SCAMP1 knockdown markedly suppressed the proliferation of GC cells in vitro and in vivo. RNA sequencing assays demonstrated that SCAMP1 knockdown altered the expression profile of GC cells, and a significant portion of the altered genes were enriched in receptor tyrosine kinases and their related downstream signaling pathways. Immunoblotting confirmed that the Akt/MAPK/Stat signaling pathway was strongly attenuated in GC cells with SCAMP1 depletion. Taken together, these results demonstrated that SCAMP1 drives hyperproliferation in GC cells, thus suggesting that further investigation into the mechanisms and translational value of SCAMP1 in treating patients with GC is warranted.

Identification of RECK as a protective prognostic indicator and a tumor suppressor through regulation of the ERK/MAPK signaling pathway in gastric cancer

BackgroundGastric cancer (GC) ranks as the fifth most common cancer worldwide and is characterized by its significant heterogeneity and unfavorable prognosis. Thus, identifying efficient prognostic factors and understanding the underlying molecular mechanisms in GC are essential for improving patient outcomes. In this study, we aimed to investigate the role of RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the prognostic significance and molecular mechanisms of its biological function in GC.MethodsMultiple bioinformatics strategies were performed to detect the potential functions and prognostic efficiency of RECK in GC. Rescue experiments revealed that the molecular mechanism by which RECK in inhibited tumor proliferation, migration, and invasion was mediated by ERK/MAPK signaling in AGS and HGC-27 cells. Using integrated bioinformatics analysis and western blot assay, we investigated the potential interaction between CALD1 and RECK.ResultsOur findings revealed significantly decreased RECK expression in GC samples compared to normal samples and RECK was identified as a promising predictor for the prognosis of GC patients. Moreover, upregulation of RECK demonstrated a distinctly positive association with a high-immunity and low-metastasis microenvironment in GC. Mechanistically, the antitumour effects of RECK on hampering tumor cell growth, migration, and invasion were mediated by the ERK/MAPK signaling pathway. In addition, we also illustrated that RECK inhibited the phosphorylation of CALD1 mediated by decreased phosphorylation of ERK.ConclusionsRECK is a promising prognostic biomarker and may shape a high-tumor-immunity and low-metastasis microenvironment in patients with GC. Moreover, RECK exerted its tumor-suppressive effects by the inactivation of ERK/MAPK signaling in GC cells.

SMYD3 Modulates the HGF/MET Signaling Pathway in Gastric Cancer.

Gastric cancer (GC) is the third most deadly cancer worldwide. Considerable efforts have been made to find targetable drivers in order to improve patient outcomes. MET is one of the most important factors involved in GC initiation and progression as it plays a major role in GC invasiveness and is related to cancer stemness. Unfortunately, treatment strategies targeting MET are still limited, with a proportion of patients responding to therapy but later developing resistance. Here, we showed that MET is a molecular partner of the SMYD3 methyltransferase in GC cells. Moreover, we found that SMYD3 pharmacological inhibition affects the HGF/MET downstream signaling pathway. Extensive cellular analyses in GC models indicated that EM127, a novel active site-selective covalent SMYD3 inhibitor, can be used as part of a synergistic approach with MET inhibitors in order to enhance the targeting of the HGF/MET pathway. Importantly, our data were confirmed in a 3D GC cell culture system, which was used as a surrogate to evaluate stemness characteristics. Our findings identify SMYD3 as a promising therapeutic target to impair the HGF/MET pathway for the treatment of GC.

Multiomics Analysis of TMEM200A as a Pan-Cancer Biomarker.

The transmembrane protein, TMEM200A, is known to be associated with human cancers and immune infiltration. Here, we assessed the function of TMEM200A in common cancers by multiomics analysis and used in vitro cell cultures of gastric cells to verify the results. The expression of TMEM200A in several human cancer types was assessed using the RNA-seq data from the UCSC Xena database. Bioinformatic analysis revealed a potential role of TMEM200A as a diagnostic and prognostic biomarker. Cultures of normal gastric and cancer cell lines were grown and TMEM200A was knocked down. The expression levels of TMEM200A were measured by using quantitative real-time polymerase chain reaction and western blotting. In vitro loss-of-function studies were then used to determine the roles of TMEM200A in the malignant behavior and tumor formation of gastric cancer (GC) cells. Western blots were used to assess the effect of the knockdown on epithelial-mesenchymal transition (EMT) and PI3K/AKT signaling pathway in GC. Bioinformatic analysis showed that TMEM200A was expressed at high levels in GC. The proliferation of GC cells was inhibited by TMEM200A knockdown, which also decreased vimentin, N-cadherin, and Snai proteins, and inhibited AKT phosphorylation. The PI3K/AKT signaling pathway also appeared to be involved in TMEM200A-mediated regulation of GC development. The results presented here suggest that TMEM200A regulates the tumor microenvironment by affecting the EMT. TMEM200A may also affect EMT through PI3K/AKT signaling, thus influencing the tumor microenvironment. Therefore, in pan-cancers, especially GC, TMEM200A may be a potential biomarker and oncogene.

Metformin promotes cGAS/STING signaling pathway activation by blocking AKT phosphorylation in gastric cancer

The cGAS/STING signaling pathway plays a pivotal role in regulating innate immunity. Emerging novel drugs aim to regulate the anti-tumor immune response by activating innate immunity. The anti-diabetic drug metformin has been reported to exhibit anti-cancer effect against various types of cancer. However, the role of metformin in regulating the cGAS/STING signaling pathway in gastric cancer remains unknown. In our study, we first used bioinformatic analysis to detect that metformin is closely related to tumor immunity in multiple tumors. Next, we validated the function of metformin in activating the cGAS/STING signaling pathway in gastric cancer cell lines. In addition, KEGG pathway enrichment analysis showed that metformin is negatively correlated with the PI3K/AKT signaling pathway in gastric cancer. We further verified that metformin activates the cGAS/STING signaling pathway by blocking AKT phosphorylation. Moreover, we found that metformin regulates the AKT signaling pathway by mediating the transcription factor SOX2. Thus, our study indicates that metformin activates the cGAS/STING signaling pathway by suppressing SOX2/AKT and has promising potential in gastric cancer immunotherapy.

CircSLC4A7 accelerates stemness and progression of gastric cancer by interacting with HSP90 to activate NOTCH1 signaling pathway

Gastric cancer stem cells (GCSCs) play critical roles in gastric cancer (GC) initiation and development. Circular RNAs (circRNAs) participate in diverse cancer biological processes and function as tumor suppressors or oncogenes. This study aims to discover the expression profile and functional roles of circRNAs in GCSCs. A spheroid formation assay was conducted to enrich GCSCs. Genome-wide sequencing of circRNAs showed that a novel circRNA, circSLC4A7, was one of the most upregulated circRNAs in GCSCs. CircSLC4A7 was localized to the nucleus, and its level was elevated in GC cells and tissues. Furthermore, circSLC4A7 increased CSC-like properties and drove cell proliferation, migration, and invasion, which were determined by gain- and loss-of-function experiments. Specific circRNA pull-down assays followed by mass spectrometry analysis, RNA immunoprecipitation, and dual RNA-fluorescence in situ hybridization and immunofluorescence assay were conducted and HSP90 was detected to interact with circSLC4A7 and mediate the oncogenic function of circSLC4A7 by activating the Notch1 signaling pathway in GC. This study highlights a novel oncogenic function of circSLC4A7 mediated by its binding with HSP90 and thus activating the Notch1 signaling pathway.

Expression of PI3K-AKT-mTOR signaling pathway in gastric cancer

Background: The PI3K/AKT/m TOR pathway is activated in gastric cancer (GC). This pathway may be an appropriate target for GC therapy. Such therapy may involve inhibiting cell proliferation, enhancing apoptosis, and restoring the sensitivity of cancer cells to chemotherapy. Aim: To study the expression of the PI3K/AKT/mTOR pathway in Egyptian patients with GC. Methods: Enrolled Patients were divided into 2 groups, group 1 included 23 patients with lymph node metastatic (LNM) gastric cancer (GC) and group 2 included 10 patients with non-metastatic GC. Liver and renal biochemical tests, CBC, H. pylori testing, CEA, CA19-9 & metastatic radiological work up were done. Upper Gastrointestinal endoscopy was done to diagnose the site, size and morphology of GC and to take biopsy from the suspicious lesion, adjacent mucosa and all parts of the stomach. Enrolled patients had received surgical resection when appropriate. The harvested tumor tissue was processed for histopathology as well as Immunohistochemical staining (IHC) for detection of expression of PI3K/AKT/mTOR. IHC score for the expression of mTOR, AKT & PI3K (ranging from 0 to 12) was calculated as follows: Grade of stain intensity × Grade of coloration rate. A score ≥4 was considered positive. Results: The mTOR expression was positive in 54.5%, AKT expression was positive in 72.7% & PI3K expression was positive in 36.4% of cases. There was significantly higher expression of AKT in metastatic (87%) than non-metastatic GC (40%), p=0.010. AKT expression was significantly higher in LNM GC (median score was 12) than non-metastatic GC (median score was 2.5), p=0.028. AKT score at cutoff value of more than 3 was a statistically significant discriminator between LNM and non-metastatic GC, AUC=0.743, p=.014, sensitivity, 87% & specificity, 60%. Conclusion: The mTOR expression was positive in 54.5%, AKT expression was positive in 72.7% & PI3K expression was positive in 36.4% of GC cases. AKT expression score may discriminate between LN metastatic and non-metastatic gastric cancer

JUNB mediates oxaliplatin resistance via the MAPK signaling pathway in gastric cancer by chromatin accessibility and transcriptomic analysis.

Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, and chemotherapy resistance is one of the main reasons for treatment failure. Thus, it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity, thereby improving the survival and prognosis of gastric cancer patients. To understand the molecular mechanisms of oxaliplatin resistance, we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) for both parental and oxaliplatin-resistant AGS cells. A total of 3232 genomic regions are identified to have higher accessibility in oxaliplatin-resistant cells, and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network. JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells, and its upregulation is associated with poor prognosis in gastric cancer patients, which is validated by our tissue microarray data. Moreover, chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that JUNB binds to the transcriptional start site of key genes involved in the MAPK signaling pathway. Knockdown of JUNB inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin. Combined treatment with the ERK inhibitor piperlongumine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance. This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway. The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin, providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.

Micro RNA-365-3p as a Tumor Suppressor in Gastric Cancer: Inhibition of NUCKS1-Mediated PI3K/AKT Signaling and Anti-Tumor Effects

Increasing evidence supports that microRNAs (miRNAs) are essential regulators of tumor initiation and development in a wide range of human malignancies, including gastric cancer (GC). To date, it has been reported that miR-365-3p is abnormally expressed and influences tumor progression in multiple malignancies. However, the roles of miR-365-3p are yet to be known and are worth investigating in GC. Herein, we screened differentially expressed miRNAs in 3 pairs of matched gastric cancerous and adjacent normal specimens. A series of public datasets and collected clinical GC samples were employed to determine the expression profiles of miR-365-3p and its downstream target protein. Furthermore, the effects of miR-365-3p ectopic expression and depletion on GC cell proliferation, invasion and migration were explored in vitro via cell counting kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU), clone formation and Transwell assays, and in vivo by applying the nude mice models. Dual-luciferase reporter, western blot and a series of rescue assays were carried out to investigate the potential interactions between miR-365-3p and NUCKS1 (Nuclear, casein kinase and cyclin-dependent kinase substrate 1) and downstream signaling pathways of the miR-365-3p/NUCKS1 axis. According to the analyses of the miRNA microarray and bioinformatics, we first identified miR-365-3p dysregulation in GC. Through miRNA qRT-PCR, we revealed that miR-365-3p was downregulated in GC samples and cell lines. Lower level of miR-365-3p was significantly associated with larger tumor size and advanced lymph node metastasis in GC patients. Downregulation of miR-365-3p accelerated, while ectopic miR-365-3p significantly suppressed GC cell proliferation, migration and invasion in vitro and in vivo. Results also showed that overexpression of miR-365-3p in gastric cancer cells significantly reduced the levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6), while miR-365-3p knockdown increased their expression. Moreover, mechanistically, knockdown of miR-365-3p promoted tumor cell aggressiveness by enhancing the expression of NUCKS1 and subsequently resulted in the activation of PI3K/AKT signaling pathway in GC. In addition, either NUCKS1 silencing or the inhibition of PI3K/AKT signaling pathway, at least partially, reversed the promotive effects of miR-365-3p knockdown on GC aggressiveness. Altogether, these findings suggest that miR-365-3p inhibits tumor growth and metastasis by attenuating the expression of NUCKS1 and inactivation of its downstream PI3K/AKT signaling, thus, highlighting the potential of miR-365-3p as a therapeutic target in GC.

SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1.

Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC.

BGN/FAP/STAT3 positive feedback loop mediated mutual interaction between tumor cells and mesothelial cells contributes to peritoneal metastasis of gastric cancer.

Peritoneal metastasis (PM) is most frequent in gastric cancer (GC) and cancer-associated fibroblasts (CAFs) play a critical role in this process. However, the concrete mechanism of crosstalk between CAFs and cancer cells in PM of GC remains unclear. Microarray sequencing of GC focus and PM lesions was performed, and biglycan (BGN) was screened for further study. Clinically, BGN expression was higher in GC tissues than adjacent normal tissues, and high expression correlated with poor prognosis. In vitro experiments demonstrated that BGN promoted tumor progression and the transformation of mesothelial cells (MCs) into cancer-associated fibroblasts like cells (CAFLCs). In turn, CAFLCs-derived fibroblast activation protein (FAP) facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells. GC-derived BGN combined with toll like receptor 2 (TLR2)/TLR4 on MCs to activate the NF-κB pathway and promote the transformation of MCs into CAFLCs by the recovery experiment, coimmunoprecipitation assay, nuclear and cytoplasmic protein extraction assay. CAFLCs-derived FAP could activate the JAK2/STAT3 signaling pathway in GC. Finally, activated STAT3 promoted BGN transcription in GC, resulting in a BGN/FAP-STAT3 positive feedback loop. Taken together, mutual interaction between tumor cells and activated MCs mediated by a BGN/FAP-STAT3 positive feedback loop facilitates PM of GC and provides a potential biomarker and therapeutic target for GC metastasis.