Oxaliplatin resistance can develop in colorectal cancer (CRC), which may involve inhibition of ferroptosis, although further research is needed to understand this potential mechanism. We evaluated CRC cells with acquired oxaliplatin resistance (HCT116-Or) or congenital resistance (H716) to determine whether a ferroptosis inducer (RSL3) or inhibitor (liproxstatin-1) could modulate the effects of oxaliplatin. The results suggested that induction of ferroptosis could significantly reverse the oxaliplatin resistance of the CRC cells. Bioinformatic and cytobiological searches also revealed that KIF20A was highly expressed in the oxaliplatin-resistant cell lines and was strongly correlated with survival among CRC patients. Silencing KIF20A enhanced cellular sensitivity to oxaliplatin both in vivo and in vitro, and silencing KIF20A also suppressed NUAK1 activation, while a NUAK1 agonist (ETC-1002) could reverse the oxaliplatin sensitivity of KIF20A-silenced cells. Moreover, silencing NUAK1 up-regulated the expression of PP1β, down-regulated the phosphorylation of downstream GSK3βSer9, suppressed the nuclear import of Nrf2, inhibited the expression of a ferroptosis key negative regulatory protein (GPX4), and blocked cellular resistance. Applying a Nrf2 agonist (oltipraz) also reversed the oxaliplatin sensitivity of NUAK1-silenced cells. Therefore, cellular ferroptosis may be inhibited via the KIF20A/NUAK1/PP1β/GPX4 pathway in CRC cells, which may underly the resistance of CRC to oxaliplatin.

Background: 5‐Fluorouracil (5‐FU) and capecitabine‐associated cardiotoxicity ranging from asymptomatic electrocardiography (ECG) abnormalities to severe myocardial infarction has been reported in a number of studies, but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date. In the present study, we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5‐FU‐ and capecitabine‐associated cardiotoxicity in cancer patients recruited from multiple centers in China. Methods: Among the 527 patients who completed the study, 196 received 5‐FU‐based chemotherapy and 331 received capecitabine‐based chemotherapy as either first‐line or adjuvant therapy. Adverse events were reported during the treatment and up to 28 days of follow‐up. Outcome measures included ECG, myocardial enzymes, cardiac troponin, brain natriuretic peptide and echocardiography. Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents. Results: In total, 161 of 527 patients (30.6%) experienced cardiotoxicity. The incidence rate of cardiotoxicity was 33.8% (112/331) in the capecitabine group, which was significantly higher than the rate of 25% (49/196) in the 5‐FU group ( P = 0.0042). 110/527 patients (20.9%) suffered arrhythmia, 105/527 (19.9%) developed ischemic changes, while only 20/527 patients (3.8%) presented heart failure and 6/527 patients (1.1%) had myocardial infarction. Pre‐existing cardiac disease, hypertension, capecitabine‐based chemotherapy and duration of treatment were identified as significant risk factors associated with cardiotoxicity. The odds ratio were 15.7 (prior history of cardiac disease versus no history), 1.86 (capecitabine versus 5‐FU), 1.06 (5–8 versus 1–4 chemotherapy cycles) and 1.58 (hypertension versus no hypertension), respectively. Conclusions: Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity. Possible risk factors are duration of treatment, capecitabine‐based chemotherapy, pre‐existing cardiac diseases and hypertension. Trial registration This study was initiated on January 22, 2014 and has been retrospectively registered with the registration number ChiCTR1800015434

Tumor heterogeneity makes early diagnosis and effective treatment of colon adenocarcinoma difficult. As an important regulator of gene expression, DNA methylation can influence tumor heterogeneity. In this study, we explored the prognostic value of subtypes based on DNA methylation status in 424 colon adenocarcinoma samples from the Cancer Genome Atlas database. Differences in DNA methylation levels were associated with differences in T, N, and M category, age, stage, and prognosis. Seven subgroups were identified based on consensus clustering using 356 CpG sites that significantly influenced survival. Finally, a prognostic model was constructed and used to classify samples in a testing dataset into seven DNA methylation subgroups based on the classification results of a training dataset. These specific classifications based on DNA methylation may help account for heterogeneity within previously established molecular subgroups of colon adenocarcinoma and could potentially aid in the development of more effective personalized treatments.

HINT2 downregulation promotes colorectal carcinoma migration and metastasis