OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway.

BACKGROUND: OCIAD2（Ovarian carcinoma immunoreactive antigen-like protein 2） is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). METHODS: The correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. RESULTS: OCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. CONCLUSIONS: In PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.

Prediction of immune infiltration and prognosis for patients with cholangiocarcinoma based on a cuproptosis-related lncRNA signature.

Objective: Cholangiocarcinoma (CHOL) is a malignant disease that affects the digestive tract, and it is characterized by a poor prognosis. This research sought to explore the involvement of cuproptosis-related lncRNAs (CRLs) in the prognostic prediction and immune infiltration of cholangiocarcinoma. Methods: The expression profiles and clinical data of CHOL patients were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and CRLs were defined via co-expression analysis. Two molecular clusters distinguished by cuproptosis-related genes (CRGs) were produced. Then a risk signature consisted by four CRLs was formed, and all samples were separated into low- and high-risk groups using a risk score. Kaplan-Meier survival analysis, principal component analysis, differentially expressed analysis, immune cell infiltration analysis, and sensitivities analysis of chemotherapy drugs were conducted between the two groups. Simultaneously, the expression values of four lncRNAs confirmed by real-time PCR in our own 20 CHOL samples were brought into the risk model. Results: The CHOL samples could be differentiated into two molecular clusters, which displayed contrasting survival times. Additionally, patients with higher risk scores had significantly worse prognosis compared to those in the low-risk group. Furthermore, both immune infiltration and enrichment analysis revealed significant discrepancies in the tumor immune microenvironment (TIME) between different risk groups. Moreover, the predictive power and the correlation with CA19-9 and CEA of risk signature were validated in our own samples. Conclusion: We developed a risk signature which could serve as an independent prognostic factor and offer a promising prediction for not only prognosis but also TIME in CHOL patients.

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer.

PURPOSE: Transglutaminases (TGs) are multifunctional enzymes exhibiting transglutaminase crosslinking, as well as atypical GTPase/ATPase and kinase activities. Here, we used an integrated comprehensive analysis to assess the genomic, transcriptomic and immunological landscapes of TGs across cancers. METHODS: Gene expression and immune cell infiltration patterns across cancers were obtained from The Cancer Genome Atlas (TCGA) database and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assays, and orthotopic xenograft models were used to validate our database-derived results. RESULTS: We found that the overall expression of TGs (designated as the TG score) is significantly upregulated in multiple cancers and related to a worse patient survival. The expression of TG family members can be regulated through multiple mechanisms at the genetic, epigenetic and transcriptional levels. The expression of transcription factors crucial for epithelial-to-mesenchymal transition (EMT) is commonly correlated with the TG score in many cancer types. Importantly, TGM2 expression displays a close connection with chemoresistance to a wide range of chemotherapeutic drugs. We found that TGM2 expression, F13A1 expression and the overall TG score were positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification revealed that a higher TGM2 expression is linked with a worse patient survival, an increased IC50 value of gemcitabine, and a higher abundance of tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, we found that increased C-C motif chemokine ligand 2 (CCL2) release mediated by TGM2 contributes to macrophage infiltration into the tumor microenvironment. CONCLUSIONS: Our results reveal the relevance and molecular networks of TG genes in human cancers and highlight the importance of TGM2 in pancreatic cancer, which may provide promising directions for immunotherapy and for addressing chemoresistance.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by poor treatment response and low survival time. The current clinical treatment for advanced PDAC is still not effective. In recent years, the research and application of immunotherapy have developed rapidly and achieved substantial results in many malignant tumors. However, the translational application in PDAC is still far from satisfactory and needs to be developed urgently. To carry out the study of immunotherapy, it is necessary to fully decipher the immune characteristics of PDAC. This review summarizes the recent progress of the tumor microenvironment (TME) of PDAC and highlights its link with immunotherapy. We describe the molecular cues and corresponding intervention methods, collate several promising targets and progress worthy of further study, and put forward the importance of integrated immunotherapy to provide ideas for future research of TME and immunotherapy of PDAC.

Exploitation and Verification of a Stroma- and Metastasis-Associated Risk Prognostic Signature in Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD), one of the most malignant tumors, not only has abundant mesenchymal components, but is also characterized by an extremely high metastatic risk. The purpose of this study was to construct a model of stroma- and metastasis-associated prognostic signature, aiming to benefit the existing clinical staging system and predict the prognosis of patients. First, stroma-associated genes were screened from the TCGA database with the ESTIMATE algorithm. Subsequently, transcriptomic data from clinical tissues in the RenJi cohort were screened for metastasis-associated genes. Integrating the two sets of genes, we constructed a risk prognostic signature by Cox and LASSO regression analysis. We then obtained a risk score by a quantitative formula and divided all samples into high- and low-risk groups based on the scores. The results demonstrated that patients with high-risk scores have a worse prognosis than those with low-risk scores, both in the TCGA database and in the RenJi cohort. In addition, tumor mutation burden, chemotherapeutic drug sensitivity and immune infiltration analysis also exhibited significant differences between the two groups. In exploring the potential mechanisms of how stromal components affect tumor metastasis, we simulated different matrix stiffness in vitro to explore its effect on EMT key genes in PAAD cells. We found that cancer cells stimulated by high matrix stiffness may trigger EMT and promote PAAD metastasis.

IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer.

BACKGROUND: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism. METHODS: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms. RESULTS: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression. CONCLUSIONS: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

Molecularly Imprinted Polymers Doped with Carbon Nanotube with Aid of Metal-Organic Gel for Drug Delivery Systems.

PURPOSE: The incidence of breast cancer worldwide has been on the rise since the late 1970s, and it has become a common tumor that threatens women's health. Aminoglutethimide (AG) is a common treatment of breast cancer. However, current treatments require frequent dosing that results in unstable plasma concentration and low bioavailability, risking serious adverse reactions. Our goal was to develop a molecularly imprinted polymer (MIP) based delivery system to control the release of AG and demonstrate the availability of this drug delivery system (DDS), which was doped with carbon nanotube with aid of metal-organic gel. METHODS: Preparation of MIP was optimized by key factors including composition of formula, ratio of monomers and drug loading concentration. RESULTS: By using multi-walled carbon nanotubes (MWCNT) and metal-organic gels (MOGs), MIP doubled the specific surface area, pore volume tripled and the IF was 1.6 times than the reference. Compared with commercial tablets, the relative bioavailability was 143.3% and a more stable release appeared. CONCLUSIONS: The results highlight the influence of MWCNT and MOGs on MIP, which has great potential as a DDS.

Green Synthesis of Carbon Nanotubes-Reinforced Molecularly Imprinted Polymer Composites for Drug Delivery of Fenbufen.

The facile fabrication of single-walled carbon nanotubes (SWCNTs)-doping molecularly imprinted polymer (MIP) nanocomposite-based binary green porogen system, room-temperature ionic liquids (RTILs), and deep eutectic solvents (DESs) was developed for drug delivery system. With fenbufen (FB) as template molecule, 4-vinylpyridine (4-VP) was used as functional monomer, ethylene glycol dimethacrylate as cross-linking monomer, and 1-butyl-3-methylimidazoliumtetrafluoroborate and choline chloride/ethylene glycol as binary green solvent, in the presence of SWCNTs. The imprinting effect of the SWCNT-MIP composites was optimized by regulation of the amount of SWCNTs, ratio of RTILs and DES, and the composition of DES. Blue shifts of UV bands strongly suggested that interaction between 4-VP and FB can be enhanced due to SWCNT doping in the process of self-assembly. The reinforced imprinted effect of CNT-doping MIP can provide superior controlled release characteristics. Compared with the control MIP prepared without SWCNTs, the imprinting factor of the SWCNT-MIP composites exhibited a twofold increase. In the analysis for the FB release kinetics from all samples, the SWCNT-reinforced MIP produced the lowest value of drug diffusivity. The relative bioavailability of the SWCNT-MIP composites (F %) displayed the highest value of 143.3% compared with the commercial FB tablet, whereas the control MIP and SWCNT-non-MIP composites was only 48.3% and 44.4%, respectively. The results indicated that the SWCNT-MIP nanocomposites developed here have potentials as the controlled-release device.