IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling.

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2+ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8+ T cells is observed in tumors with up-regulated BST2+ macrophages. Mechanistically, BST2+ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8+ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2+ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8+ T cell exhaustion in PDAC.

Cell of Origin of Pancreatic cancer: Novel Findings and Current Understanding.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal diseases globally, boasting a grim 5-year survival prognosis. The origin cell and the molecular signaling pathways that drive PDAC progression are not entirely understood. This review comprehensively outlines the categorization of PDAC and its precursor lesions, expounds on the creation and utility of genetically engineered mouse models used in PDAC research, compiles a roster of commonly used markers for pancreatic progenitors, duct cells, and acinar cells, and briefly addresses the mechanisms involved in the progression of PDAC. We acknowledge the value of precise markers and suitable tracing tools to discern the cell of origin, as it can facilitate the creation of more effective models for PDAC exploration. These conclusions shed light on our existing understanding of foundational genetically engineered mouse models and focus on the origin and development of PDAC.

STRAP as a New Therapeutic Target for Poor Prognosis of Pancreatic Ductal Adenocarcinoma Patients Mainly Caused by TP53 Mutation.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and poor prognosis. KRAS, TP53, CDKN2A, and SMAD4 are driver genes of PDAC and 30-75% patients have mutations in at least two of these four genes. Herein, we analyzed the relationship between these genes and prognosis of 762 patients in the absence of coexisting mutations, using data from three independent public datasets. Interestingly, we found that compared with mutations in other driver genes, TP53 mutation plays a significant role in leading to poor prognosis of PDAC. Additionally, we found that snoRNA-mediated rRNA maturation was responsible for the progression of cancer in PDAC patients with TP53 mutations. Inhibition of STRAP, which regulates the localization of SMN complexes and further affects the assembly of snoRNP, can effectively reduce maturation of rRNA and significantly suppress progression of TP53-mutant or low p53 expression pancreatic cancer cells in vitro and in vivo. Our study highlighted the actual contribution rate of driver genes to patient prognosis, enriching traditional understanding of the relationship between these genes and PDAC. We also provided a possible mechanism and a new target to combat progression of TP53-mutant PDAC patients.

Upregulation of CENPM facilitates tumor metastasis via the mTOR/p70S6K signaling pathway in pancreatic cancer.

Pancreatic cancer is a severe disease with high morbidity and mortality. However, the primary molecular mechanisms of pancreatic tumor formation and progression remain unclear. The present study using sequencing technology revealed that the centromere protein M (CENPM) gene was overexpressed in pancreatic cancer tissues. CENPM is one of the components of a complex that plays a central role in kinetochore protein assembly, mitotic progression and chromosome segregation. However, the biological function of CENPM in pancreatic cancer has yet to be determined. Hence, two effective siRNAs were designed to knock down CENPM. Notably, downregulation of CENPM inhibited pancreatic cancer cell proliferation, altered the cell cycle and limited pancreatic cancer cell migration and invasion via the mTOR/p70S6K signaling pathway. This research provides new evidence that CENPM overexpression plays a significant role in the progression of pancreatic cancer. Overall, the present findings indicated that CENPM may be a significant biomarker for predicting the development and progression of pancreatic malignancy.

KRT17 Functions as a Tumor Promoter and Regulates Proliferation, Migration and Invasion in Pancreatic Cancer via mTOR/S6k1 Pathway.

BACKGROUND: Pancreatic cancer (PC) is one of the most well-known malignancies with high mortality, but the underlying mechanism of PC remains unknown. Keratin17 (KRT17) expression has been reported in many malignancies, but its functions in PC are not clear. The aim of our study was to evaluate KRT17 expression and its potential role in PC. METHODS: The online databases GEPIA and THPA were used to identify KRT17 expression in tissues. Quantitative real-time PCR (qRT-PCR) was used to determine KRT17 expression in cell lines. Ki67 and ROS levels were detected by immunofluorescence assay and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. KRT17 downregulation was induced by the small interfering RNA (siRNA) technique. Proliferation function was evaluated by colony formation assay and RTCA. Migration and invasion were evaluated by transwell migration assay. A Western blot assay was used to detect protein levels. RESULTS: KRT17 was overexpressed in PC tissues compared to that in normal tissues. The results showed that Ki67 and ROS levels were decreased in pancreatic cancer cells after transfection with siKRT17. After KRT17 downregulation in PC cell lines, cell viability functions, including proliferation, migration and invasion, and mTOR/S6K1 phosphorylation levels were attenuated. CONCLUSION: KRT17 knockdown significantly inhibited proliferation, migration and invasion in pancreatic cancer cells.

Adipose­derived mesenchymal stem cells ameliorate dibutyltin dichloride­induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway.

Adipose­derived mesenchymal stem cells (ASCs) play a positive role in tissue injury repair and regeneration. The aim of this study was to determine whether ASCs could ameliorate chronic pancreatitis (CP) induced by the injection of dibutyltin dichloride (DBTC) and to elucidate its potential mechanisms. Furthermore, this study also explored whether there was a significant difference if the ASCs were injected via the inferior vena cava or the left gastric artery. CP was induced in rats by a single intravenous administration of DBTC, and the accumulation of collagen and apoptotic rates of pancreatic acinar cells were analyzed. According to the results, ASCs markedly reduced DBTC­induced pancreatic damage and collagen deposition in the rat model of CP. Moreover, ASCs significantly decreased pancreatic cell apoptosis by regulating the expression levels of caspase­3, BAX and Bcl­2. These effects were observed regardless of whether the injection was in the inferior vena cava or the left gastric artery. It was also found that the expression levels of phosphorylated PI3K, AKT and mTOR in pancreatic tissues of the DBTC­induced CP model group were significantly increased, while the expression levels of phosphorylated PI3K, AKT and mTOR in the two treatment groups were markedly decreased. ASCs noticeably suppressed the PI3K/AKT/mTOR pathway in the pancreatic tissue of DBTC­induced CP. This study indicated that ASCs protect against pancreatic fibrosis by modulating the PI3K/AKT/mTOR pathway, and have the potential to be a new strategy for the treatment of CP in the future.

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma.

The promoter methylation mode of microribonucleic acid (miRNA) plays a crucial role in the process of hepatocellular carcinoma (HCC). Therefore, the primary purpose of this study was to screen and verify the miRNA methylation sites associated with the overall survival (OS) and clinical characteristics of HCC patients. Methylation-related data were from the Cancer Genome Atlas (TCGA). R software was utilized to screen the methylation sites. The least absolute shrinkage and selection operator algorithm was utilized to develop the miRNA promoter methylation models. Then, methylation-specific polymerase chain reaction was performed with 146 HCC tissues to verify the accuracy of the vascular infiltration-related model. Additionally, we verified the functions of vascular infiltration-related miRNA by utilizing cells transfected with miR-199a-3p mimic. The model for predicting OS of HCC patients contained eight methylation sites. The Kaplan-Meier analysis suggested that the model could divide HCC patients into high- and low-risk groups (P < .0001). COX regression analysis suggested that the model (P < .001; 95% CI, 1.264-2.709) and T category (P < .001; 95% CI, 1.472-3.119) were independent risk factors for affecting OS of HCC patients. The model for predicting vascular infiltration, pathological grade, and clinical stage contained 7, 10, and 9 methylation sites respectively, with their area under the receiver operating characteristic curve (AUC) values 0.667, 0.745, and 0.725, respectively. The functional analysis suggested that miRNA methylation is involved in various biological processes such as WNT, MAPK, and mTOR signaling pathways. The accuracy of the vascular infiltration-related model was consistent with our previous bioinformatics assay. And upregulation of miR-199a-3p decreased migration and invasion abilities. The screened miRNA promoter methylation sites can be served as biomarkers for judging OS, vascular infiltration, pathology grade, and clinical stage. It can also provide new targets for improving the treatment and prognosis of HCC patients.

DPP4 Inhibitor Attenuates Severe Acute Pancreatitis-Associated Intestinal Inflammation via Nrf2 Signaling.

Severe acute pancreatitis (SAP) is a challenging disease with high morbidity and mortality, often complicated by multiple organ dysfunction syndrome (MODS). The intestine, a major organ involved in MODS, correlates strongly with the evolution of the disease. In this study, we demonstrated that the DPP4 inhibitor, sitagliptin, protects SAP-associated intestinal injury both in vitro and in vivo. These beneficial effects were achieved by suppressing oxidative stress and inflammatory responses. Moreover, in sitagliptin-treated SAP mice, expression of Nrf2 was induced and that of NF-κB was reduced, compared to the control SAP mice. In addition, we used Nrf2-/- mice to test the protective effect of Nrf2 during sitagliptin treatment of SAP; our results indicated that Nrf2-/- mice had greater pancreatic and intestinal injury than wild-type mice. Taken together, high levels of ROS induced by SAP may be inhibited by sitagliptin, possibly by inactivating the Nrf2-NF-κB pathway.

Baohuoside I Inhibits the Proliferation of Pancreatic Cancer Cells via mTOR/S6K1-Caspases/Bcl2/Bax Apoptotic Signaling.

BACKGROUND: Although the incidence of pancreatic cancer has increased markedly, the 5-year survival rate for this disease is considerably low compared with other types of cancer. Moreover, the mortality rate of pancreatic cancer is similar to its incidence rate. Current therapeutic agents exhibit a lack of specificity for pancreatic cancer. Baohuoside I is traditionally used to treat orgasmic disorder and inflammation. However, its role in pancreatic cancer is unknown. OBJECTIVE: To explore the effects of Baohuoside I on pancreatic cancer and to study the potential-related molecular mechanism. MATERIALS AND METHODS: In the present study, the antineoplastic effect of Baohuoside I was investigated with regard to pancreatic cancer via colony formation, transwell and migration assay. The energy metabolism changes of pancreatic cancer were tested by flow cytometry analysis and oxidative phosphorylation and glycolysis assay. The target signaling members were analyzed by Western blot. RESULTS: Baohuoside I inhibited the cell growth of pancreatic cancer cells. In addition, it affected intracellular energy metabolism to induce cancer cell apoptosis via the mTOR/S6K1 and the caspase/Bcl2/Bax signaling pathways. CONCLUSION: The present data provide further insight into the development of novel drugs against pancreatic cancer.