Phosphoproteomics reveals that cinobufotalin promotes intrahepatic cholangiocarcinoma cell apoptosis by activating the ATM/CHK2/p53 signaling pathway.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that originates from bile duct's epithelial cells and is usually characterized by insidious symptoms and poor prognosis. Cinobufotalin (CB), an active ingredient obtained from the Traditional Chinese Medicine ChanSu, is purported to exhibit a wide range of antitumorigenic activities. However, the mechanism by which it achieves such pharmacological effects remains elusive. Here, we disclosed the mechanism of action by which CB inhibits ICC cells. Initial experiments revealed that the proliferation of RBE and HCCC-9810 cells was significantly inhibited by CB with IC50 values of 0.342 µM and 0.421 µM respectively. CB induced the expression of caspase-3 subsequently leading to the apoptosis of ICC cells. Phosphoproteomics revealed that the phosphorylation of many proteins associated with DNA damage response increased. Kinase-substrate enrichment analysis revealed that ATM was activated after CB treatment, while CDK1 was inactivated. Activated ATM increased p-CHK2-T68 and p-p53-S15, which promoted the expression of FAS, DR4 and DR5 and triggered cell apoptosis. In summary, this work reveals the role of CB in inducing DNA damage and cell apoptosis involved in the activation of the ATM/CHK2/p53 signaling pathway, and indicates that CB may serve as a chemotherapeutic drug candidate for ICC treatment.

The N6-Methyladenosine Modification and Its Role in mRNA Metabolism and Gastrointestinal Tract Disease.

The N6-methyladenosine (m6A) modification is the most abundant internal modification of messenger RNA (mRNA) in higher eukaryotes. Under the actions of methyltransferase, demethylase and methyl-binding protein, m6A resulting from RNA methylation becomes dynamic and reversible, similar to that from DNA methylation, and this effect allows the generated mRNA to participate in metabolism processes, such as splicing, transport, translation, and degradation. The most common tumors are those found in the gastrointestinal tract, and research on these tumors has flourished since the discovery of m6A. Overall, further analysis of the mechanism of m6A and its role in tumors may contribute to new ideas for the treatment of tumors. m6A also plays an important role in non-tumor diseases of the gastrointestinal tract. This manuscript reviews the current knowledge of m6A-related proteins, mRNA metabolism and their application in gastrointestinal tract disease.

High serum uric acid may associate with the increased risk of colorectal cancer in females: A prospective cohort study.

Elevated serum uric acid (SUA) levels have been previously reported to play a role in multiple types of cancers. However, epidemiological studies evaluating SUA levels and colorectal cancer risk remain sparse. This cohort study included 444 462 participants between the ages of 40 and 69 years from the UK Biobank, followed up from 2006 to 2010. Multivariable adjusted Cox regression models were used to estimate hazard ratios (HRs). During a mean follow-up of 6.6 years, 2033 and 855 cases of colon and rectal cancers, respectively, were diagnosed. The multivariable-adjusted HRs for risks of colon cancer in the lowest uric acid categories (≤3.5 mg/dL) compared with the reference groups were 1.31 (95% confidence interval [CI] = 0.75-2.29) in males and 1.26 (95% CI = 1.03-1.55) in females. The HRs in the highest uric acid groups (>8.4 mg/dL) were 1.16 (95% CI = 0.83-1.63) in males and 2.00 (95% CI = 1.02-3.92) in females. The corresponding HRs of rectal cancer in the lowest uric acid groups compared with the reference group were 2.21 (95% CI = 1.15-4.23) in males and 0.98 (95% CI = 0.66-1.45) in females. The HRs in the highest uric acid groups were 1.35 (95% CI = 0.82-2.23) in males and 3.81 (95% CI = 1.38-10.56) in females. In conclusion, SUA showed a U-shaped association with colon cancer risk in both male and female populations. The same pattern was observed in male patients with rectal cancer. However, SUA levels were positively associated with occurrence of rectal cancer in female subjects.

A pancreas tumor derived organoid study: from drug screen to precision medicine.

Pancreatic ductal adenocarcinoma (PDAC) one of the deadliest malignant tumor. Despite considerable progress in pancreatic cancer treatment in the past 10 years, PDAC mortality has shown no appreciable change, and systemic therapies for PDAC generally lack efficacy. Thus, developing biomarkers for treatment guidance is urgently required. This review focuses on pancreatic tumor organoids (PTOs), which can mimic the characteristics of the original tumor in vitro. As a powerful tool with several applications, PTOs represent a new strategy for targeted therapy in pancreatic cancer and contribute to the advancement of the field of personalized medicine.