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.
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.
Pancreatic Neoplasms , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Apoptosis/genetics , Pancreatic Neoplasms/genetics , Cell Death , Tumor Microenvironment/genetics , Pancreatic Neoplasms
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.
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Tumor Microenvironment , Pancreatic Neoplasms/pathology , Immunotherapy/methods , Carcinoma, Pancreatic Ductal/pathology , Immunosuppression Therapy , Pancreatic Neoplasms
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.
