High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment.

BACKGROUND: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment. METHODS: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding Protein (RBP) Immunoprecipitation]-seq were used to confirm the potential regulating role of peptidyl-tRNA hydrolase 1 homolog (PTRH1) on the stability of the PD-L1 mRNA. Postoperative specimens were used to identify the expression of PD-L1 and PTRH1 in pancreatic cancer. Co-culturing T cells with pancreatic cancer cells to explore the immunosuppressive effect of pancreatic tumor cells. RESULTS: Our results revealed that a high dose of glucose enhanced the stability of the PD-L1 mRNA in pancreatic tumor cells by downregulating PTRH1 through RAS signaling pathway activation following epidermal growth factor receptor (EGFR) stimulation. PTRH1 overexpression significantly suppressed PD-L1 expression in pancreatic cells and improved the proportion and cytotoxic function of CD8+ T cells in the pancreatic TME of diabetic mice. CONCLUSIONS: PTRH1, an RBP, plays a key role in the regulation of PD-L1 by high glucose and is closely related to anti-tumor immunity in the pancreatic TME.

METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner.

In eukaryotes, N6-methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Hyperglycemia Enhances Immunosuppression and Aerobic Glycolysis of Pancreatic Cancer Through Upregulating Bmi1-UPF1-HK2 Pathway.

BACKGROUND & AIMS: Accumulating evidence strongly suggests that hyperglycemia promotes the progression of pancreatic cancer (PC). Approximately 80% of patients with PC are intolerant to hyperglycemic conditions. In this study, we define the role of Bmi1, a stemness-related oncogene, in controlling the Warburg effect, and immune suppression under hyperglycemia conditions. METHODS: The diabetes mellitus model was established by intraperitoneal injection of streptozotocin. The role of the hyperglycemia-Bmi1-HK2 axis in glycolysis-related immunosuppression was examined in both orthotopic and xenograft in vivo models. Evaluation of immune infiltrates was carried out by flow cytometry. Human PC cell lines, SW1990, BxPC-3, and CFPAC-1, were used for mechanistic in vitro studies. RESULTS: Through bioinformatics analysis, we found that hyperglycemia was strongly related to aerobic glycolysis, immunosuppression, and cancer cell stemness. High glucose condition in the tumor microenvironment promotes immune suppression by upregulating glycolysis in PC cells, which can be rescued via knockdown Bmi1 expression or after 2-deoxy-D-glucose treatment. Through gain-/loss-of-function assessments, we found that Bmi1 upregulated the expression of UPF1, which enhanced the stability of HK2 mRNA and thereby increased the expression of HK2. The role of the hyperglycemia-Bmi-HK2 pathway in the inhibition of antitumor immunity was further verified via the immune-competent and immunodeficient mice model. We also demonstrated that hyperglycemia promotes the expression of Bmi1 by elevating the intracellular acetyl-CoA levels and histone H4 acetylation levels. CONCLUSIONS: Our results suggest that the previously unreported Bmi1-UPF1-HK2 pathway contributes to PC progression and immunosuppression, which may bring in new targets for developing effective therapies to treat patients with PC.

A novel staging system and clinical predictive nomogram for more accurate staging and prognosis of malignant pancreatic intraductal papillary mucinous neoplasms: a population-based study.

BACKGROUND: The current guidelines of the American Joint Committee on Cancer (AJCC) for the staging of exocrine pancreatic tumors seem inapplicable to malignant pancreatic intraductal papillary mucinous neoplasms (IPMN). Therefore, we aimed to improve the accuracy of clinical staging and prognosis for malignant IPMN by modifiing current AJCC system. METHODS: We extracted data of 2001 patients with malignant IPMN from the Surveillance, Epidemiology, and End Results database between 2000 and 2016. Of these, 1401 patients were assigned to the primary cohort and 600 patients to the validation cohort. RESULTS: In Kaplan-Meier analysis of the primary cohort, the current AJCC guidelines were unable to distinguish between certain tumor substages (IA and IB in the 7th, IB and IIA in the 8th). The modified system that we regrouped based on the median overall survival and hazard ratios, was superior in tumor stage classifications. Age > 70 years, tumors located in the body or tail, high-grade differentiated tumors, surgery, chemotherapy, and tumor, lymph node, and metastasis (TNM) stage were identified as independent predictive factors for overall survival. Compared to that of TNM-based systems, the concordance index of the clinical predictive nomogram significantly improved (0.819; 95% confidence interval, 0.805-0.833), with excellent area under the receiver operating characteristic curves (1-, 3-, and 5-year: 0.881, 0.889, and 0.879, respectively). The calibration curves also showed good agreement between prediction and actual observation. The analysis of treatment modalities revealed that surgery resulted in better survival for all resectable malignant IPMN. The analysis of chemotherapy data reveals its potential in improving the prognosis of treatment for patients with locally advanced or distant metastases. CONCLUSIONS: Our modified staging system improves the distinction of tumor stages. The nomogram was a more accurate and clinically reliable tool for prognosis prediction of patients with malignant IPMN.

Characterization of METTL7B to Evaluate TME and Predict Prognosis by Integrative Analysis of Multi-Omics Data in Glioma.

Glioma is the most common and aggressive type of primary brain malignant tumor with limited treatment approaches. Methyltransferase-like 7B (METTL7B) is associated with the pathogenesis of several diseases but is rarely studied in glioma. In this study, 1,493 glioma samples (data from our cohort, TCGA, and CGGA) expressing METTL7B were used to explore its prognostic value and mechanism in the immune microenvironment. Results showed that high expression of METTL7B is associated with poor prognosis and abundant immunosuppressive cells. Further, functional enrichment showed that METTL7B is involved in the negative regulation of immunity and carcinogenic signaling pathways. Moreover, a METTL7B-related prognostic signature constructed based on multi-omics showed a good prediction of the overall survival (OS) time of glioma patients. In conclusion, METTL7B is a potential prognostic biomarker. In addition, the prognostic prediction model constructed in this study can be used in clinical setups for the development of novel effective therapeutic strategies for glioma patients and improving overall survival.

Characterization of Hypoxia Signature to Evaluate the Tumor Immune Microenvironment and Predict Prognosis in Glioma Groups.

Glioma groups, including lower-grade glioma (LGG) and glioblastoma multiforme (GBM), are the most common primary brain tumor. Malignant gliomas, especially glioblastomas, are associated with a dismal prognosis. Hypoxia is a driver of the malignant phenotype in glioma groups; it triggers a cascade of immunosuppressive processes and malignant cellular responses (tumor progression, anti-apoptosis, and resistance to chemoradiotherapy), which result in disease progression and poor prognosis. However, approaches to determine the extent of hypoxia in the tumor microenvironment are still unclear. Here, we downloaded 575 LGG patients and 354 GBM patients from Chinese Glioma Genome Atlas (GGGA), and 530 LGG patients and 167 GBM patients from The Cancer Genome Atlas (TCGA) with RNA sequence and clinicopathological data. We developed a hypoxia risk model to reflect the immune microenvironment in glioma and predict prognosis. High hypoxia risk score was associated with poor prognosis and indicated an immunosuppressive microenvironment. Hypoxia signature significantly correlated with clinical and molecular features and could serve as an independent prognostic factor for glioma patients. Moreover, Gene Set Enrichment Analysis showed that gene sets associated with the high-risk group were involved in carcinogenesis and immunosuppression signaling. In conclusion, we developed and validated a hypoxia risk model, which served as an independent prognostic indicator and reflected overall immune response intensity in the glioma microenvironment.

Sulphur doped carbon dots enhance photodynamic therapy via PI3K/Akt signalling pathway.

OBJECTIVES: Photodynamic therapy (PDT) is a promising approach for cancer treatment, and the underlying signalling pathway changes has been carried out for studying the PDT mechanisms, but is majorly limited to organic photosensitizers (PSs). For the emerging nano-PSs typically possessing higher 1 O2 quantum yield, few mechanistic studies were carried out, which limited their further applications in clinical therapeutics. PI3K/Akt signalling pathway, a most frequently activated signalling network in cancers, could promote cancer cell survival, but was seldom reported in previous PDT studies mediated by nano-PSs. MATERIALS AND METHODS: Sulphur doped carbon dots (S-CDs) was prepared via a hydrothermal synthetic route and was characterized by transmission electron microscopy, X-ray photoelectron spectroscopy and so on. CCK-8 assay and Annexin V/PI staining were performed to demonstrate the death of cancer cells, Western blot, RT-PCR and immunofluorescence were employed to explore the underlying mechanism, and variation of PI3K/Akt and other signalling pathways was detected by Western blot. RESULTS: S-CDs was successfully synthesized, and it was much more efficient compared with classic organic PSs. S-CDs could induce cancer cell death through mitochondria mediated cell apoptosis with the imbalance of Bcl-2 family proteins and caspase cascade via several signalling pathways. Low concentration of S-CDs could effectively inhibit PI3K/Akt pathway and promote p38/JNK pathway, on one way inhibiting cancer cell survival and on the other way promoting cell apoptosis. CONCLUSIONS: Herein, we found that S-CDs acted as an inhibitor of the PI3K/Akt pathway for efficient cancer cell killing, thus yielding in a higher PDT performance over the existing photosensitizers.

Overexpression of YBX1 Promotes Pancreatic Ductal Adenocarcinoma Growth via the GSK3B/Cyclin D1/Cyclin E1 Pathway.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers due to frequently late diagnosis and futile treatment. It is a crucial necessity to determine the mechanisms of PDAC. Y-box Binding Protein 1 (YBX1), a highly conserved transcription factor, has been previously reported to play a role in various hallmarks of cancer. We show here that YBX1 is significantly overexpressed in PDAC and correlates with poor prognosis and reduced survival. In PDAC cell lines, YBX1 regulated cell-cycle progression, proliferation, and the expression of glycogen synthase kinase 3 beta (GSK3B) and cell-cycle-related proteins cyclin D1 and E1. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays established that YBX1 binds to the promoter of GSK3B, suggesting that YBX1 promotes pancreatic cancer cell growth through induction of GSK3B expression. These findings offer important insights into the mechanisms underlying pathologic proliferation in PDAC.

Radiation-induced small extracellular vesicles as "carriages" promote tumor antigen release and trigger antitumor immunity.

Rationale: Accumulating evidence supports the importance of radiation therapy in the induction of antitumor immunity. Small extracellular vesicles (sEVs) play essential roles in tumor antigen loading and delivery. However, the role of sEVs in radiation-induced antitumor immunity remains unclear. It is therefore important to determine the role and regulatory mechanisms of sEVs in radiation-induced immunity. Methods: Tumor cells were irradiated (8 Gy), and sEVs were purified via ultracentrifugation. Primary tumor and experimental lung metastasis models were established in mice to evaluate antitumor immunity triggered by immunization with sEVs. Proteomic and bioinformatic analyses were performed to identify altered cargos in sEVs induced by radiation. Peptides derived from up-regulated proteins in sEVs were designed and synthesized as vaccines according to major histocompatibility complex (MHC) I binding and immunogenicity. Results: Here, we demonstrated that sEVs derived from irradiated tumor cells could trigger antitumor immunity against primary tumor and experimental lung metastasis by enhancing CD8+ and CD4+ T cell infiltration. Radiation may also enrich sEVs with tumor antigens and heat-shock proteins. Furthermore, CUB domain-containing protein 1 (CDCP1) derived from radiation-induced sEVs was identified as a novel tumor-associated antigen and developed as a peptide vaccine that may generate antitumor immune responses. Conclusions: Our results demonstrate that the use of sEVs secreted by irradiated tumor cells constitutes an efficient approach for tumor antigen delivery and presentation and highlight the role of sEVs in radiation-triggered antitumor immunity.

Nucleoside-based fluorescent carbon dots for discrimination of metal ions.

Carbon dots (Cdots) play an important role in many biological and chemical applications. To prepare strongly fluorescent Cdots, the starting material should contain nitrogen in addition to carbon. Nucleobases are nitrogen rich with interesting metal binding properties. In this work, we prepared a series of Cdots with citrate as the carbon source, and ethylenediamine, adenosine, cytidine, thymidine or guanosine as the respective nitrogen sources. The resulting Cdots were all fluorescent with the ethylenediamine sample being the most strongly emissive. These Cdots were then tested for their metal sensitivity and all tested metal ions can quench their fluorescence. The fluorescence of the G-Cdots prepared with guanosine was quenched most efficiently by Cu2+, while the Cdots prepared with ethylenediamine were more sensitive to Hg2+. With the differential quenching by different metal ions, we prepared a sensor array to discriminate multiple metal ions, and quantified Cu2+ and Hg2+ at the same time. Our work has expanded the range of starting materials for preparing Cdots and showed that by tuning the precursor composition, Cdots with different optical and metal binding properties can be obtained, which is useful in constructing a sensing platform for a large number of metal ions.

ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer.

Poor prognosis in pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM). Glucose metabolism has been revealed to contribute to the therapeutic resistance and pluripotent state of PanCa cells. However, few studies have focused on the effects of GEM on cancer cell metabolism, stemness of tumor cells, and molecular mechanisms that critically influence PanCa treatment. We demonstrate that GEM treatment induces metabolic reprogramming, reducing mitochondrial oxidation and upregulating aerobic glycolysis, and promotes stem-like behaviors in cancer cells. Inhibiting aerobic glycolysis suppresses cancer cell stemness and strengthens GEM's cytotoxicity. GEM-induced metabolic reprogramming is KRAS dependent, as knockdown of KRAS reverses the metabolic shift. GEM-induced metabolic reprogramming also activates AMP-activated protein kinase (AMPK), which promotes glycolytic flux and cancer stemness. In addition, GEM-induced reactive oxygen species (ROS) activate the KRAS/AMPK pathway. This effect was validated by introducing exogenous hydrogen peroxide (H2O2). Taken together, these findings reveal a counterproductive GEM effect during PanCa treatment. Regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming might be effective approaches to eliminate cancer stem cells (CSCs) and enhance chemosensitivity to GEM to improve the prognosis of PanCa patients.

A Population-Based Study of the Incidence and Survival of Anorectal Gastrointestinal Stromal Tumor.

BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common type of primary gastrointestinal mesenchymal tumor, but GISTs arising in the anus and rectum are rare. This study aimed to undertake a population-based analysis of the incidence, patient demographics, and survival of patients with anorectal GIST compared with patients with GIST arising from other sites based on the Surveillance, Epidemiology, and End Results (SEER) Program database. MATERIAL AND METHODS The SEER database was used to identify all patients diagnosed with GIST and patients diagnosed with anorectal GIST from 2000 to 2015. The incidence of GIST, baseline clinical and demographic data, tumor stage, and patient survival data were analyzed, including overall survival (OS) and cancer-specific survival (CSS). RESULTS A total of 277 patients with anorectal GIST were identified, with an incidence of 0.018 per 100,000. The incidence of GIST arising from other sites was 0.719 per 100,000. The median age at diagnosis for anorectal GIST was 57.5 years (range, 26-92 years), median tumor size was 6.55 cm (range, 0.6-20 cm), and surgery, but not chemotherapy, improved OS and CSS. Patients with anorectal GIST had a mean 1-year, 3-year, 5-year, and 10year OS of 91.1%, 82.5%, 75.2%, and 58.5%, respectively. Patients with GIST arising at other sites had a mean 1-year, 3-year, 5-year, and 10-year OS of 88.3%, 76.4%, 66.5%, and 46.8%, respectively. CONCLUSIONS Anorectal GIST is a rare tumor that has a better outcome compared with GISTs arising at other sites in the gastrointestinal tract.

Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells.

BACKGROUND: Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed in clinical settings in attempt to reduce the chance of developing therapeutic resistance. Valproic acid (VPA) has been reported as a promising anticancer drug in various clinical trials and studies. However, the clinical value and potential dose-effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated. RESULTS: In this study, we determined the synergistic effect of VPA and gemcitabine and found that high-dose VPA significantly and dose-dependently enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Intriguingly, low-dose VPA potentiated the migration and invasion of pancreatic cancer cells that already showed gemcitabine-induced motility. Moreover, low-dose VPA increased the reactive oxygen species (ROS) production, which activated AKT to further stimulate the activation of STAT3, Bmi1 expression and eventually promoted the migration and invasion of pancreatic cancer cells induced by gemcitabine. Whereas high-dose VPA stimulated excessive ROS accumulation that promoted p38 activation, which suppressed the activation of STAT3 and Bmi1. CONCLUSION: Pancreatic cancer cells respond differentially towards low- or high-dose of VPA in combination with gemcitabine, and a low VPA further potentiate pancreatic cancer cell to migrate and invade. Our results suggest that STAT3/Bmi1 signaling cascade, which is regulated by ROS-dependent, AKT- or p38-modulated pathways, primarily mediated the sensitivity and motility of pancreatic cancer cells towards combined gemcitabine and VPA regimen. These findings suggest a highly clinically relevant new mechanism of developing resistance against combined chemo-regimens, warranting further mechanistic and translational exploration for VPA in combination with gemcitabine and other chemotherapies.

High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway.

BACKGROUND: Modulation of cell surface expression of MHC class I chain-related protein A/B (MICA/B) has been proven to be one of the mechanisms by which tumor cells escape from NK cell-mediated killing. Abnormal metabolic condition, such as high glucose, may create a cellular stress milieu to induce immune dysfunction. Hyperglycemia is frequently presented in the majority of pancreatic cancer patients and is associated with poor prognosis. In this study, we aimed to detect the effects of high glucose on NK cell-mediated killing on pancreatic cancer cells through reduction of MICA/B expression. METHODS: The lysis of NK cells on pancreatic cancer cells were compared at different glucose concentrations through lactate dehydrogenase release assay. Then, qPCR, Western Blot, Flow cytometry and Immunofluorescence were used to identify the effect of high glucose on expression of MICA/B, Bmi1, GATA2, phosphorylated AMPK to explore the underlying mechanisms in the process. Moreover, an animal model with diabetes mellitus was established to explore the role of high glucose on NK cell-mediated cytotoxicity on pancreatic cancer in vivo. RESULTS: In our study, high glucose protects pancreatic cancer from NK cell-mediated killing through suppressing MICA/B expression. Bmi1, a polycomb group (PcG) protein, was found to be up-regulated by high glucose, and mediated the inhibition of MICA/B expression through promoting GATA2 in pancreatic cancer. Moreover, high glucose inhibited AMP-activated protein kinase signaling, leading to high expression of Bmi1. CONCLUSION: Our findings identify that high glucose may promote the immune escape of pancreatic cancer cells under hyperglycemic tumor microenvironment. In this process, constitutive activation of AMPK-Bmi1-GATA2 axis could mediate MICA/B inhibition, which may serve as a therapeutic target for further intervention of pancreatic cancer immune evasion.

Colonic Gastrointestinal Stromal Tumor: A Population-Based Analysis of Incidence and Survival.

OBJECTIVES: The incidence of gastrointestinal stromal tumors (GISTs) located in the colon is rare. Current studies mainly focus on case reports for colonic GISTs. Therefore, a population-based analysis was useful to guide the clinical treatment strategy. METHODS: The patients were selected from 2000 to 2015 based on Surveillance, Epidemiology, and End Results (SEER) database. Patients' demographics, tumor characteristics, incidence, treatment, and survival were retrieved for analysis. RESULTS: 249 cases of colonic GISTs were collected. The male-female ratio was close to 1 : 1 (male 51.41%, female 48.59%). Most cases were Caucasians (70.28%), and African Americans accounted for 19.68%. Age of diagnosis ranged from 21 to 93 years with a median (mean) age of 67.5 (65.56). The incidence was rare, only 0.018 per 100,000. It had an annual percentage change (APC = -0.7728) without statistical significance (P = 0.5127) while the incidence of other GISTs increased from 2000 to 2015, with an annual percentage change of 3.9% (P = 0.0001). Surgery was associated with better prognosis whereas chemotherapy did not impact the survival rate. CONCLUSION: Colonic GIST is a rare solid tumor, and the incidence is stable. The entity has a poorer prognosis than other GISTs. Surgery improved the survival rate, while chemotherapy did not.

Tumor location as an indicator of survival in T1 resectable pancreatic ductal adenocarcinoma: a propensity score-matched analysis.

BACKGROUND: The latest 8th edition of the AJCC staging system emphasizes the importance of tumor size however, the clinical significance of the combination of tumor location with tumor size remains unknown. METHODS: We conducted this study to investigate the prognostic role of tumor location in T1 resectable pancreatic ductal adenocarcinoma (PDAC). Resectable PDAC patients from Surveillance, Epidemiology, and End Results (SEER) database (2004-2014) were selected for the propensity score matching analysis. We used matched cohort to analyze the relationship between clinicopathologic features and survival of patients. RESULT: Eight thousand, four hundred nine patients were included in the propensity score matching analysis and 4571 patients were selected for final analysis. In T1 patients, the patients with pancreatic head tumor had worse prognosis compared to the patients with body/tail tumors. Multivariate analysis result showed that pancreatic body/tail location was an independent indicator for better chances of survival in T1 PDAC patients (hazard ratio, 0.69; 95%CI, 0.52-0.93; P = 0.01). The modified staging system was more efficient than the AJCC 8th staging system. CONCLUSION: Modified staging system exhibited a good assessment of the survival rate. The tumor location is a good prognostic indicator for T1 resectable PDAC patients. Modification of T1 subgroup according to tumor location exhibited favorable survival prediction effects.

B7-H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. PDAC is resistant to chemotherapy and radiotherapy which leads to the poor prognosis of PDAC patients and a 5-year survival rate of less than 5%. Exploring the mechanism of the pancreatic cancer tumorigenesis is the key to finding a novel therapeutic strategy for cancer treatment. B7-H3 belongs to the B7 family of immunoregulatory proteins, and the overexpression of B7-H3 is found in various types of cancer. The regulation of B7-H3 expression in pancreatic cancer is still unclear. Here, we showed that B7-H3 acted as a negative prognostic biomarker in PDAC and promoted cell proliferation, invasion and metastasis in pancreatic cancer. Next, we applied the drug screening method to identify bromodomain and extra-terminal motif (BET) inhibitors that decreased the protein and mRNA levels of B7-H3 in pancreatic cancer cells. Moreover, we verified that BRD4 was responsible for regulating the expression of B7-H3 at the transcriptional level. Finally, our data indicated that the BRD4/B7-H3 axis modulated the expression of TLR4 in pancreatic cancer cells. Taken together, our results elucidated the regulation of B7-H3 expression in pancreatic cancer and uncovered the importance of BRD4/B7-H3/TLR4 pathway. The targeting of B7-H3 by the BET inhibitors may be a novel therapeutic strategy to overcome the immunotherapy and chemotherapy resistance in pancreatic cancer.