Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

From clinical variables to multiomics analysis: a margin morphology-based gross classification system for hepatocellular carcinoma stratification.

OBJECTIVE: Selecting interventions for patients with solitary hepatocellular carcinoma (HCC) remains a challenge. Despite gross classification being proposed as a potential prognostic predictor, its widespread use has been restricted due to inadequate studies with sufficient patient numbers and the lack of established mechanisms. We sought to investigate the prognostic impacts on patients with HCC of different gross subtypes and assess their corresponding molecular landscapes. DESIGN: A prospective cohort of 400 patients who underwent hepatic resection for solitary HCC was reviewed and analysed and gross classification was assessed. Multiomics analyses were performed on tumours and non-tumour tissues from 49 patients to investigate the mechanisms underlying gross classification. Inverse probability of treatment weight (IPTW) was used to control for confounding factors. RESULTS: Overall 3-year survival rates varied significantly among the four gross subtypes (type I: 91%, type II: 80%, type III: 74.6%, type IV: 38.8%). Type IV was found to be independently associated with poor prognosis in both the entire cohort and the IPTW cohort. The four gross subtypes exhibited three distinct transcriptional modules. Particularly, type IV tumours exhibited increased angiogenesis and immune score as well as decreased metabolic pathways, together with highest frequency of TP53 mutations. Patients with type IV HCC may benefit from adjuvant intra-arterial therapy other than the other three subtypes. Accordingly, a modified trichotomous margin morphological gross classification was established. CONCLUSION: Different gross types of HCC showed significantly different prognosis and molecular characteristics. Gross classification may aid in development of precise individualised diagnosis and treatment strategies for HCC.

Quenching thirst with poison? Paradoxical effect of anticancer drugs.

Anticancer drugs have been developed with expectations to provide long-term or at least short-term survival benefits for patients with cancer. Unfortunately, drug therapy tends to provoke malignant biological and clinical behaviours of cancer cells relating not only to the evolution of resistance to specific drugs but also to the enhancement of their proliferation and metastasis abilities. Thus, drug therapy is suspected to impair long-term survival in treated patients under certain circumstances. The paradoxical therapeutic effects could be described as 'quenching thirst with poison', where temporary relief is sought regardless of the consequences. Understanding the underlying mechanisms by which tumours react on drug-induced stress to maintain viability is crucial to develop rational targeting approaches which may optimize survival in patients with cancer. In this review, we describe the paradoxical adverse effects of anticancer drugs, in particular how cancer cells complete resistance evolution, enhance proliferation, escape from immune surveillance and metastasize efficiently when encountered with drug therapy. We also describe an integrative therapeutic framework that may diminish such paradoxical effects, consisting of four main strategies: (1) targeting endogenous stress response pathways, (2) targeting new identities of cancer cells, (3) adaptive therapy- exploiting subclonal competition of cancer cells, and (4) targeting tumour microenvironment.

Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells.

The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly sensitive to disturbances that lead to ER stress. In response, the unfolded protein response (UPR) activates to restore ER homeostasis, primarily through three sensors: IRE1, ATF6, and PERK. ERAD and autophagy are crucial in mitigating ER stress, yet their dysregulation can lead to the accumulation of misfolded proteins. Cisplatin, a commonly used chemotherapy drug, induces ER stress in tumor cells, activating complex signaling pathways. Resistance to cisplatin stems from reduced drug accumulation, activation of DNA repair, and anti-apoptotic mechanisms. Notably, cisplatin-induced ER stress can dualistically affect tumor cells, promoting either survival or apoptosis, depending on the context. ERAD is crucial for degrading misfolded proteins, whereas autophagy can protect cells from apoptosis or enhance ER stress-induced apoptosis. The complex interaction between ER stress, cisplatin resistance, ERAD, and autophagy opens new avenues for cancer treatment. Understanding these processes could lead to innovative strategies that overcome chemoresistance, potentially improving outcomes of cisplatin-based cancer treatments. This comprehensive review provides a multifaceted perspective on the complex mechanisms of ER stress, cisplatin resistance, and their implications in cancer therapy.

Associations of cholecystectomy with the risk of colorectal cancer: a Mendelian randomization study.

BACKGROUND: Cholecystectomy is a standard surgery for patients suffering from gallbladder diseases, while the causal effects of cholecystectomy on colorectal cancer (CRC) and other complications are still unknown. METHODS: We obtained genetic variants associated with cholecystectomy at a genome-wide significant level ( P value <5 × 10 -8 ) as instrumental variables (IVs) and performed Mendelian randomization (MR) to identify the complications of cholecystectomy. Furthermore, the cholelithiasis was also treated as the exposure to compare its causal effects to those of cholecystectomy, and multivariable MR analysis was carried out to judge whether the effect of cholecystectomy was independent of cholelithiasis. The study was reported based on Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines. RESULTS: The selected IVs explained 1.76% variance of cholecystectomy. Our MR analysis suggested that cholecystectomy cannot elevate the risk of CRC (odds ratio [OR] =1.543, 95% confidence interval [CI]: 0.607-3.924). Also, it was not significant in either colon or rectum cancer. Intriguingly, cholecystectomy might decrease the risk of Crohn's disease (OR = 0.078, 95% CI: 0.016-0.368) and coronary heart disease (OR = 0.352, 95% CI: 0.164-0.756). However, it might increase the risk of irritable bowel syndrome (IBS) (OR = 7.573, 95% CI: 1.096-52.318). Cholelithiasis could increase the risk of CRC in the largest population (OR = 1.041, 95% CI: 1.010-1.073). The multivariable MR analysis suggested that genetic liability to cholelithiasis could increase the risk of CRC in the largest population (OR = 1.061, 95% CI: 1.002-1.125) after adjustment of cholecystectomy. CONCLUSIONS: The study indicated that cholecystectomy might not increase the risk of CRC, but such a conclusion needs further proving by clinical equivalence. Additionally, it might increase the risk of IBS, which should be paid attention to in clinical practice.

Diet-derived antioxidants and nonalcoholic fatty liver disease: a Mendelian randomization study.

BACKGROUND: Whether supplementation with diet-derived antioxidants is beneficial for nonalcoholic fatty liver disease (NAFLD) is still controversial and we hope to answer this question using population-based genetic data. METHODS: A total of 8485 NAFLD cases and 658,849 healthy controls from four independent NAFLD genome-wide association studies were enrolled in this study. Genetic variants closely associated with the diet-derived antioxidants were selected to predict their circulating levels. A bi-directional Mendelian randomization (MR) design was employed to assess their causations. RESULTS: Genetic correlation analyses suggested inverse associations between diet-derived antioxidants and NAFLD. MR analyses indicated that the odds ratio (OR) of per standard deviation increase in genetically predicted toenail and blood selenium was 1.179 for NAFLD (95% confidence interval [1.083-1.284]). Also, the genetically elevated selenium level was causally associated with increased levels of C-reactive protein, fibrinogen, alkaline phosphatase and glycated hemoglobin. The OR of 1 µg/dL increase in genetically predicted serum lycopene was 1.082 (95%CI [1.051-1.113]). No other causal associations were found for NAFLD. However, we observed protective effects of genetically predicted ß-carotene (OR = 0.929[0.911-0.947]) and retinol (OR = 0.483[0.460-0.508]) on type 2 diabetes (T2D), and further they could reduce the serum levels of blood lipids and glucose. Reverse MR analysis suggested genetically predicated NAFLD status would not affect the levels of diet-derived antioxidants. CONCLUSION: Overall, we observed the positive associations of genetically predicted selenium and lycopene with NAFLD. However, the genetically predicted ß-carotene and retinol levels were inversely associated with the risk of T2D.

Examination on the risk factors of cholangiocarcinoma: A Mendelian randomization study.

Background: Several risk factors have been identified for CCA, however, whether such associations were causal remains unknown. Methods: Mendelian randomization (MR) has been applied to examine the causal relationship between 26 putative risk factors and CCA. The genetic variants for each risk factor were extracted from their corresponding genome-wide association study (GWAS) if they reached the genome-wide significance (p-value < 5 × 10-8). The genetic associations with CCA were obtained from the publicly available GWAS with the largest sample size. Mainly, inverse-variance weighted (IVW) has been adopted to estimate the causal effect on CCA. Both multivariable and mediation MR analyses were carried out to detect independent factors. Results: Three putative risk factors can causally elevate the risk of CCA after FDR correction, including liver fat content (LFC), non-alcoholic fatty liver disease (NAFLD), and cholelithiasis. The odds of CCA would increase per 1-SD increase in the liver fat content (LFC) (OR = 2.12 [1.66, 2.71]) and logOR of NAFLD. The genetic liability to cholelithiasis would increase the risk of CCA as well (OR = 2.17 [1.47, 3.20]). They were still significant in other methods. The multivariable MR analysis indicated that genetically-elevated LFC should increase the risk of CCA independently of cholelithiasis (OR = 1.88 [1.39, 2.55]). In the mediation MR analysis, the indirect effect was not significant when treating cholelithiasis as the mediator (indirect OR = 0.95 [0.85, 1.07]). Conclusion: This MR study identified that gallstone and liver fat accumulation are two independent risk factors of CCA, suggesting two modifiable ways of preventing CCA.