AbstractChondrodysplasia is closely associated with low birth weight and increased susceptibility to osteoarthritis in adulthood. Prenatal prednisone exposure (PPE) can cause low birth weight; however, its effect on offspring cartilage development remains unexplored. Herein, rats are administered clinical doses of prednisone intragastrically on gestational days (GDs) 0–20 and underwent long‐distance running during postnatal weeks (PWs) 24–28. Knee cartilage is assayed for quality and related index changes on GD20, PW12, and PW28. In vitro experiments are performed to elucidate the mechanism. PPE decreased cartilage proliferation and matrix synthesis, causing offspring chondrodysplasia. Following long‐distance running, the PPE group exhibited more typical osteoarthritis‐like changes. Molecular analysis revealed that PPE caused cartilage circRNomics imbalance in which circGtdc1 decreased most significantly and persisted postnatally. Mechanistically, prednisolone reduced circGtdc1 expression and binding with Srsf1 to promote degradation of Srsf1 via K48‐linked polyubiquitination. This further inhibited the formation of EDA/B+Fn1 and activation of PI3K/AKT and TGFβ pathways, reducing chondrocyte proliferation and matrix synthesis. Finally, intra‐articular injection of offspring with AAV‐circGtdc1 ameliorated PPE‐induced chondrodysplasia, but this effect is reversed by Srsf1 knockout. Altogether, this study confirms that PPE causes chondrodysplasia and susceptibility to osteoarthritis by altering the circGtdc1‐Srsf1‐Fn1 axis; in vivo, overexpression of circGtdc1 can represent an effective intervention target for ameliorating PPE‐induced chondrodysplasia.

Background: Primary liver cancer (PLC) ranks third in terms of fatality rate among all malignant tumors worldwide. Proteomics and metabolomics have become widely utilized in identifying causes and diagnostic indicators of PLC. Nevertheless, in studies aiming to identify proteins/metabolites that experienced significant changes before PLC, the potential impact of reverse causation and confounding variables still needs to be fully addressed. Methods: This study thoroughly investigated the causal relationship between 4719 blood proteins, 21 amino acids, and the risk of PLC using the Mendelian randomization (MR) method. In addition, through a comprehensive analysis of the TCGA-LIHC cohort and GEO databases, we evaluated the differentially expressed genes (DEGs) related to serine metabolism in diagnosing and predicting the prognosis of patients with PLC. Results: A total of 63 proteins have been identified as connected to the risk of PLC. Additionally, there has been confirmation of a positive cause–effect between PLC and the concentration of serine. The integration of findings from both MR analyses determined that the protein associated with PLC risk exhibited a significant correlation with serine metabolism. Upon careful analysis of the TCGA-LIHC cohort, it was found that eight DEGs are linked to serine metabolism. After thoroughly validating the GEO database, two DEGs, TDO2 and MICB, emerged as potential biomarkers for diagnosing PLC. Conclusions: Two proteins involved in serine metabolism, MICB and TDO2, are causally linked to the risk of PLC and could potentially be used as diagnostic indicators.

Aims: Amoxicillin is a broad-spectrum beta-lactam antibiotic used to treat infectious diseases in pregnant women. Studies have shown that prenatal amoxicillin exposure (PAmE) has developmental toxicity on fetal development. However, the effect of PAmE on long bone development has not been reported. This study aimed to investigate the "toxic window" of PAmE on long bone development and explore its possible mechanism in fetal mice. Materials and methods: Pregnant mice were administered amoxicillin by gavage at different stages (gestational day (GD)10-12 and GD16-18), different doses (150 and 300 mg/kg & sdot;d) and different courses (single and multiple courses). Fetal femurs were collected at GD18 and bone development related indicators were detected. Key findings: The results showed that PAmE significantly reduced the length of the femur and primary ossification center of fetal mice, and inhibited the development of fetal growth plate. Meanwhile, PAmE inhibited the development of bone marrow mesenchymal stem cells, osteoclasts and endothelial cells in fetal long bone. Further, we found the fetal long bone developmental toxicity induced by PAmE was most significant at latepregnancy (GD16-18), high dose (300 mg/kg & sdot;d) and multiple-course group. Besides, PAmE inhibited the expression of Wnt/beta-catenin signaling pathway in fetal long bone. The beta-catenin mRNA expression was significantly positively correlated with the development indexes of fetal long bone. Significance: PAmE has toxic effects on long bone development, and there was an obvious "toxic window" of PAmE on the long bone development in fetal mice. The Wnt/beta-catenin signaling pathway may mediate PAmEinduced fetal long bone development inhibition.

Owing to the presence of microbial biofilm on the implant, the eradication of biofilm-associated infections poses a challenge for antibiotic therapies. The study aimed to investigate the efficacy and safety of the novel antibiotic agent TNP-2092 in the context of implant infections. In vivo, rats with periprosthetic joint infection (PJI) treated with antibiotics showed an increase in body weight and decrease in swelling, temperature, and width of knee, compared with the control group. Meanwhile, inflammatory markers in synovium and serum were decreased in the TNP-2092 group, consistent with the pathological results. Moreover, TNP-2092 was effective in eliminating bacteria and disruption biofilm formation, and further alleviated the abnormal bone absorption and reactive bone changes around the prosthesis. In conclusion, intra-articular injection of TNP-2092 is safe and effective in treating knee PJI in a rat model. The study provides a foundation for the future utilization of TNP-2092 in the management of implant-related infections.

Background: Immune infiltration-related genes have reported to play important roles in the prognosis of cholangiocarcinoma (CHOL). This study aimed to screen for prognostic markers of CHOL and construct a prognostic prediction model based on prognostic markers. Methods: Immune cell infiltration was evaluated in CHOL tumor samples using the single sample Gene Set Enrichment Analysis (ssGSEA) algorithm, followed by immune clustering grouping. Based on immune grouping, differentially expressed genes (DEGs) were selected, and the prognostic markers of CHOL were screened from these DEGs through Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) algorithm. A survival prognostic prediction model was constructed and validated based on the prognostic markers of CHOL. Results: The samples were divided into two clusters, and 349 intersection DEGs were identified between the tumor and normal and cluster 2 groups and cluster 1 comparison groups, which were enriched in immune response, inflammatory response, and cytokine-cytokine receptor interaction-related functions and pathways. Based on these genes, six DEGs were screened to construct a prognostic risk prediction model. In the training and validation datasets, there was a significant correlation between the actual prognosis and the different risk groups of the samples divided based on the prediction model. Conclusion: Our study established a prognostic signature associated with immune cell infiltration in patients with CHOL. This prognostic model may be used for diagnosis and prognosis of this disease.

BACKGROUND The difference in the prognoses between treatment with surgical therapy and continuation of local-plus-systemic therapy following successful down-staging of intermediate-advanced hepatocellular carcinoma (HCC) remains unclear. METHODS Data of 405 patients with intermediate-advanced HCC treated at 30 hospitals across China from January 2017 to July 2022 were retrospectively reviewed. All patients received local-plus-systemic therapy and were divided into the surgical (n = 100) and nonsurgical groups (n = 305) according to whether they received surgical therapy. The differences between long-term prognoses of the 2 groups were compared. Subgroup analysis was performed in 173 HCC patients who met the criteria for surgical resection following down-staging. RESULTS Multivariable analysis of all patients showed that surgical therapy, hazard ratio (HR): 0.289, 95% confidence interval, CI, 0.136-0.613) was a protective factor for overall survival (OS), but not for event-free survival (EFS). Multivariable analysis of 173 intermediate-advanced HCC patients who met the criteria for surgical resection after conversion therapy showed that surgical therapy (HR: 0.282, 95% CI, 0.121-0.655) was a protective factor for OS, but not for EFS. Similar results were obtained after propensity score matching. For patients with Barcelona Clinic Liver Cancer stage B (HR: 0.171, 95% CI, 0.039-0.751) and C (HR: 0.269, 95% CI, 0.085-0.854), surgical therapy was also a protective factor for OS. CONCLUSIONS Overall, for patients with intermediate-advanced HCC who underwent local-plus-systemic therapies, surgical therapy is a protective factor for long-term prognosis and can prolong OS, and for those who met the surgical resection criteria after conversion therapy, surgical therapy is recommended.

Metabolic dysregulation is emerging as a critical factor in tumorigenesis, and reprogramming of serine metabolism has been identified as an essential factor in the progression of hepatocellular carcinoma (HCC). Studies have shown that LKB1 deficiency can activate mTOR to upregulate the serine synthesis pathway (SSP) and promote tumor progression. Our team discovered that ubiquitin-specific protease 10 (USP10) can inhibit HCC proliferation through mTOR, but its relationship with SSP needs further investigation. The metabolite assays revealed a significant increase in serine content in HCC tissues. Through the LKB1/mTOR/activating transcription factor 4 (ATF4) axis, loss of USP10 may increase serine biosynthesis and promote the proliferation of HCC in vitro and in vivo. Furthermore, it was found that USP10 could activate LKB1 through deubiquitination. Analyzing clinical HCC tissues revealed a positive correlation between USP10 and LKB1. Additionally, those with high expression of USP10 in HCC tissues showed a better degree of tumor differentiation and longer overall survival time. Moreover, we found increased expression of both serine and its synthase in liver tumor tissues of USP10 liver-specific KO mice. Loss of USP10 inhibits the activity of LKB1, contributing to the stimulation of the mTOR/ATF4 axis and SSP and then promoting the proliferation of HCC. This work presents a novel approach for serine-targeted treatment in HCC.

Background. Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer, and the therapy options for PDAC remain restricted. The distinctive tumor immunological microenvironment (TIME) of PDAC, comprising a high number of stromal cells and a limited infiltration of cytotoxic T lymphocytes (CTLs), rendered immunotherapy ineffective. The protein level of ubiquitin-specific protease 43 (USP43) was a prognostic predictor in numerous cancers; however, its function in PDAC is limited. This article focuses on the influence of USP43 expression on PDAC prognosis and TIME alteration. Methods. Based on TCGA database and tissue microarray staining, the expression of USP43 in PDAC was evaluated. The association between USP43 and prognosis was then investigated using tissue samples and online databases. In PDAC tumor tissues, the correlation between USP43 expression and clinicopathological characteristics, immune cell infiltration, and prognosis was investigated. The expression of USP43 in PDAC cell lines was evaluated using quantitative polymerase chain reaction. Using a cell counting kit-8 (CCK-8) and a cell colony formation test, the viability of the cells was determined. On the basis of online databases and tissue samples, the link between USP43 and immune cell infiltration around PDAC was also examined. For statistical analyses, the software GraphPad, R, and SPSS 26.0 were utilized. Results. The expression of USP43 was considerably higher in PDAC compared to normal pancreatic tissue in both the TCGA database and the tissue microarrays of PDAC patients (P<0.001). High USP43 expression was associated with poor overall survival in both the TCGA database and the tissue microarray of PDAC patients (P=0.046 and 0.021, respectively). USP43 overexpression promoted PANC-1 cell proliferation (P=0.0018), but USP43 knockdown decreased PANC02 cell proliferation (P<0.001). According to the TCGA database, USP43 is associated with T cell activation and inhibits CD8+ T cell activation in PDAC, as proven by a study of cell lines. Moreover, in both TCGA and PDAC cell lines, USP43 expression was negatively linked with the chemokine signaling pathway. Conclusions. Overexpression of USP43 is a potential prognostic indicator for PDAC patients. USP43 is a potential biomarker associated with T cell activation, suppression of CD8+ T cell enrichment, and the cytokine signal pathway. Future multicenter studies are needed to confirm our findings and their potential application in the treatment of PDAC patients.

Alternative polyadenylation (APA) plays a major role in controlling transcriptome diversity and therapeutic resistance of cancers. However, long non-coding RNAs (lncRNAs) involved in pathological APA remain poorly defined. Here, we functionally characterize LINC00921, a MED13L/P300-induced oncogenic lncRNA, and show that it is required for global regulation of APA in non-small cell lung cancer (NSCLC). LINC00921 shows significant potential for reducing NSCLC radiosensitivity, and high LINC00921 levels are associated with a poor prognosis for patients with NSCLC treated with radiotherapy. LINC00921 controls NUDT21 stability by facilitating binding of NUDT21 with the E3 ligase TRIP12. LINC00921-induced destabilization of NUDT21 promotes 3 ' UTR shortening of MED23 mRNA via APA, which, in turn, leads to elevated MED23 protein levels in cancer cells and nuclear translocation of beta-catenin and thereby activates expression of multiple beta-catenin/T cell factor (TCF)/lymphoid enhancer-binding factor (LEF)-regulated core oncogenes (c-Myc, CCND1, and BMP4). These findings highlight the importance of functionally annotating lncRNAs controlling APA and suggest the clinical potential of therapeutics for advanced NSCLC.

Abstract Profilin 2 (PFN2) is an actin-binding protein important for cancer initiation and progression. However, the function and precise role of PFN2 in non-small cell lung cancer (NSCLC) remain unclear. Here, we assessed the expression levels of PFN2 in tissue from patients with NSCLC; identified binding partners using mass spectrometry, co-immunoprecipitations, and molecular modeling; and studied the angiogenic-promoting function of PFN2 using 3D droplet cultures and tube-formation assays. We found that upregulated PFN2 expression is associated with poor prognosis in patients with NSCLC. Knockdown of PFN2 significantly impaired the proliferation and angiogenesis of NSCLC cells, both in vivo and in vitro. Mechanistically, PFN2 physically interacts with pyruvate kinase M2 (PKM2) and modulates extracellular-signal regulated kinase 1/2 (ERK1/2)-mediated phosphorylation of PKM2 at S37, which substantially increases its nuclear translocation. PFN2 knockdown lead to reduced expression of PKM2, p65-NF-κB, and hypoxia-inducible factor (HIF)-1α and inhibited the nuclear translocation of PKM2. This resulted in impaired formation of the PKM2-HIF-1α-p65-NF-κB transcription complex, leading to decreased expression of its downstream target genes VEGFA, CCND1, and MAP2K5. Moreover, mutations in PFN2 at Y134 or S138 impaired its binding to PKM2, nuclear translocation of PKM2, and functionally inhibited angiogenesis in lung cancer cells. Overall, our data provide insights into the role of PFN2 in the regulation of lung cancer angiogenesis and indicate that PFN2 may serve as a therapeutic target against NSCLC.

Lymph node metastases are commonly observed in diverse malignancies where they promote cancer progression and poor outcomes, although the molecular basis is incompletely understood. Thyroid cancer is the most prevalent endocrine neoplasm characterized by high frequency of lymph node metastases. Here, we uncover an inflammatory cytokines-controlled epigenetic program during thyroid cancer progression. LNCPTCTS acts as a novel tumor suppressive lncRNA with remarkably decreased expression in thyroid cancer specimens, especially in metastatic lymph nodes. Inflammatory cytokines TNFα or CXCL10, which are released from tumor microenvironment (TME), impair binding capabilities of the transcription factor (TF) EGR1 to the LNCPTCTS promoter and reduce the lncRNA expression in cells. Notably, LNCPTCTS binds to eEF1A2 protein and facilitates the interaction between eEF1A2 and Snail, which promotes Snail nucleus export via the RanGTP-Exp5-aa-tRNA-eEF1A2 complex. Loss of LNCPTCTS in tumors leads to accumulation of Snail in the nucleus, suppressed transcription of E-cadherin and PEBP1, reduced E-cadherin and PEBP1 protein levels, and activated epithelial-mesenchymal transition and MAPK signaling. Our results reveal what we believe to be a novel paradigm between TME and epigenetic reprogram in cancer cells which drives lymph node metastases, therefore illuminating the suitability of LNCPTCTS as a targetable vulnerability in thyroid cancer.

<p>Table S1 shows primers for RT-qPCR. Table S2 shows sequences of shRNAs and siRNAs. Table S3 shows antibodies used in the study. Table S4 shows the sequence of the biotin-labeled probes for circPDIA4 and controls. Table S5 shows the overlap circRNAs of the three gastric cancer cell lines. Table S6 shows the relevant clinic-pathological characteristics of gastric cancer cases stratified by circPDIA4 levels in Combined cohort. Table S7 shows the relevant clinic-pathological characteristics of gastric cancer cases stratified by QKI levels in Combined cohort. Table S8 shows Mass Spectrometry of proteins pulled-down by circPDIA4 in HGC-27 cells.</p>

背景与目的:胰腺淋巴上皮囊肿(PLEC)是一种罕见的胰腺囊性病变,其临床表现无明显特异性,术前影像学诊断较为困难,与其他胰腺良恶性病变鉴别有一定难度,其确诊仍然依赖术后病理组织学检查.迄今为止,PLEC作为胰腺良性肿瘤,未出现临床症状的患者多建议保守治疗,出现明显临床症状或与恶性肿瘤鉴别不清者需行外科手术治疗.本文介绍1例PLEC的临床表现、诊断及鉴别诊断要点、临床治疗路径和病理组织学特征;并通过国内外相关文献阅读,总结其临床特征,以期为提高PLEC的诊疗水平提供借鉴和参考.方法:回顾性分析了 2021年7月大连医科大学附属大连市中心医院肝胆外科诊治的1例PLEC临床资料.结果:患者为59岁男性,因体检意外发现胰腺肿物入院,增强核磁共振扫描可见胰腺颈部大小为2.6 cm×4.3 cm椭圆形异常信号.通过讨论分析患者临床表现、影像学特征、实验室检查结果等方面资料,认为有手术指征和条件,遂行胰十二指肠切除.手术时间360min,术中出血50mL.术后病理组织学检查确诊为PLEC.术后患者未出现出血、胰瘘、感染、胃排空障碍等并发症.术后10d拔除引流管,术后12d出院.结论:PLEC是一种罕见的胰腺囊性良性病变,由于其临床表现不典型,术前诊断较为困难.有症状的胰腺囊性病患者通常需要行外科手术完整切除病变组织,对于无法明确PLEC诊断的患者,建议行外科手术治疗,患者术后通常预后良好;无症状者可考虑保守治疗和随访观察.

Background: Severe acute pancreatitis (SAP) is a severe form of acute pancreatitis with the potential to cause life-threatening complications. Patients with acute SAP require surgical intervention and are admitted to the intensive care unit for non-invasive ventilation. Dexmedetomidine (Dex) is currently used by intensive care clinicians and anaesthesiologists as an adjunctive sedative. Therefore, the clinical availability of Dex makes it easier to implement in SAP treatment than developing new drugs. Methods: Randomly dividing thirty rats into sham-operated (Sham), SAP, and Dex groups. The severity of pancreatic tissue injury in each rat was assessed by Hematoxylin and eosin (HE) staining. Serum amylase activity and inflammatory factor levels were measured using commercially available kits. The expressions of necroptosis-related proteins, myeloperoxidase (MPO), CD68, and 4-hydroxy-trans-2-nonenal (HNE) were detected using immunohistochemistry (IHC). Transferase-mediated dUTP nick-end labeling (TUNEL) staining was utilized to identify pancreatic acinar cell apoptosis. The subcellular organelle structure of pancreatic acinar cells was observed using transmission electron microscopy. The regulatory effect of Dex on the gene expression profile of SAP rat pancreas tissue was investigated using RNA sequencing. We screened for differentially expressed genes (DEGs). Quantitative real-time PCR (qRT-PCR) measured critical DEG mRNA expression in rat pancreatic tissues. Results: Dex attenuated SAP-induced pancreatic injury, infiltration of neutrophils and macrophages, and oxidative stress. Dex inhibited the expression of necroptosis-associated proteins RIPK1, RIPK3, and MLKL and alleviated apoptosis in acinar cells. Dex also mitigated the structural damage caused by SAP to mitochondria and endoplasmic reticulum. Dex inhibited SAP-induced 473 DEGs, as determined by RNA sequencing. Dex may regulate SAP-induced inflammatory response and tissue damage by inhibiting the toll-like receptor/nuclear factor κB (TLR/NF-κB) signaling pathway and neutrophil extracellular trap formation. Conclusion: This study elucidated the remarkable effect of Dex against SAP and investigated the potential mechanism of action, providing an experimental base for the future clinical application of Dex in the treatment of SAP.

BACKGROUND:Gastric cancer remains the leading cause of cancer death in the world. It is increasingly evident that long non-coding RNAs (lncRNAs) transcribed from the genome-wide association studies (GWAS)-identified gastric cancer risk loci act as a key mode of cancer development and disease progression. However, the biological significance of lncRNAs at most cancer risk loci remain poorly understood.METHODS:The biological functions of LINC00240 in gastric cancer were investigated through a series of biochemical assays. Clinical implications of LINC00240 were examined in tissues from gastric cancer patients.RESULTS:In the present study, we identified LINC00240, which is transcribed from the 6p22.1 gastric cancer risk locus, functioning as a novel oncogene. LINC00240 exhibits the noticeably higher expression in gastric cancer specimens compared with normal tissues and its high expression levels are associated with worse survival of patients. Consistently, LINC00240 promotes malignant proliferation, migration and metastasis of gastric cancer cells in vitro and in vivo. Importantly, LINC00240 could interact and stabilize oncoprotein DDX21 via eliminating its ubiquitination by its novel deubiquitinating enzyme USP10, which, thereby, promote gastric cancer progression.CONCLUSIONS:Taken together, our data uncovered a new paradigm on how lncRNAs control protein deubiquitylation via intensifying interactions between the target protein and its deubiquitinase. These findings highlight the potentials of lncRNAs as innovative therapeutic targets and thus lay the ground work for clinical translation.

Figure S1 shows elevated expression of circPDIA4 in gastric cancer tissues and impacts on viability of gastric cancer cells. Figure S2 shows that circPDIA4 enhanced invasive activities of gastric cancer cells. Figure S3 shows that circPDIA4 enhanced invasive activities of gastric cancer cells. Figure S4 shows that transcriptional factor SP1 plays an important role in up-regulating QKI expression in gastric cancer. Figure S5 shows that ERK1/2 interacts with circPDIA4 and phosphorylated ERK1/2 protein co-localizes with DUSP6 in gastric cancer. Figure S6 shows impacts of circPDIA4 on effects of different ERK inhibitors in gastric cancer. Figure S7 shows that silenced circPDIA4 promoted the suppression of cell viability induced by silencing of MAPK1 expression. Figure S8 shows that circPDIA4 facilitated oncogenic circRNAs formation depending on the RNA helicase DHX9 in gastric cancer.

Osteoarthritis (OA) is an age-related metabolic disease. Low-grade inflammation and oxidative stress are the last common pathway of OA. α-ketoglutarate (α-KG) is an essential physiological metabolite from the mitochondrial tricarboxylic acid (TCA) cycle, with multiple functions, including anti-inflammation and antioxidation, and exhibits decreased serum levels with age. Herein, we aimed to investigate the effect and mechanism of α-KG on OA. We first quantified the α-KG levels in human cartilage tissue and osteoarthritic chondrocytes induced by IL-1β. Besides, IL-1β-induced osteoarthritic chondrocytes were treated with different concentrations of α-KG. Chondrocyte proliferation and apoptosis, synthesis and degradation of extracellular matrix, and inflammation mediators were analyzed. RNA sequencing was used to explore the mechanism of α-KG, and mitophagy and oxidative stress levels were further detected. These results were verified in an anterior cruciate ligament transection (ACLT) induced age-related OA rat model. We found that α-KG content decreased by 31.32% in damaged medial cartilage than in normal lateral cartilage and by 36.85% in IL-1β-induced human osteoarthritic chondrocytes compared to control. α-KG supplementation reversed IL-1β-induced chondrocyte proliferation inhibition and apoptosis, increased the transcriptomic and proteinic expression of ACAN and COL2A1 in vivo and in vitro, but inhibited the expression of MMP13, ADAMTS5, IL-6, and TNF-α. In mechanism, α-KG promoted mitophagy and inhibited ROS generation, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Overall, α-KG content decreased in human OA cartilage and IL-1β-induced osteoarthritic chondrocytes. Moreover, α-KG supplementation could alleviate osteoarthritic phenotype by regulating mitophagy and oxidative stress, suggesting its potential as a therapeutic target to ameliorate OA.

Abstract Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRNA in gastric cancer. Clinically, circPDIA4 was significantly upregulated in malignant tissues and was associated with poor survival of patients with gastric cancer. The biogenesis of circPDIA4 was mediated by the RNA-binding protein Quaking, which bound introns 2 and 4 of PDIA4 pre-mRNA to promote backsplicing of exons 3 and 4. Elevated expression of circPDIA4 promoted distant metastasis in various mouse xenograft models in vivo and accelerated cancer cell invasion in vitro. CircPDIA4 functioned through distinct oncogenic mechanisms in the cytoplasm and the nucleus. Cytoplasmic circPDIA4 bound to ERK1/2 and sustained hyperactivation of the MAPK pathway by preventing DUSP6-mediated ERK1/2 dephosphorylation. Notably, circPDIA4 depletion enhanced the sensitivity of gastric cancer cells to ERK inhibitors. In the nucleus, circPDIA4 interacted with DHX9 as a decoy and repressed its inhibitory functions on circRNA biogenesis to boost expression of multiple oncogenic circRNAs, which promoted gastric cancer progression. These findings reveal a dual tumor-promoting mechanism for circPDIA4 by regulating oncogenic circRNA biogenesis and increasing MAPK activity. CircPDIA4 should be investigated further as a potential prognostic biomarker and therapeutic target in gastric cancer. Significance: Quaking-regulated circPDIA4 mediates different mechanisms in the nucleus and cytoplasm that coordinate to promote progression and drug resistance in gastric cancer.