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.

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.

BackgroundLaparoscopic total gastrectomy (LTG) with Roux-en-Y (RY) is often accompanied by a series of complications. Uncut RY (URY) can effectively reduce Roux stasis syndrome (RSS) in laparoscopic distal gastrectomy. To determine whether totally LTG (TLTG) with URY for gastric cancer (GC) can replace RY in short-term and long-term prognosis.MethodsThis comparative retrospective study selected GC patients from 2016 to 2022. The patients were divided into URY group and RY group. Cox multivariate proportional hazard regression analysis was used to explore the independent prognostic factors. Propensity score matching (PSM) was used to reduce bias.ResultsA total of 100 GC patients met the inclusion criteria. Compared to RY group, URY group showed significant advantages in operation time and length of hospital stay. In addition, URY group can significantly reduce short-term and long-term complications, especially RSS. The 1-, 3- and 5-year progression free survival (PFS) of URY group and RY group were 90.4% vs. 67.8% (P=0.005), 76.6% vs. 52.6% (P=0.009) and 76.6% vs. 32.8% (P<0.001), respectively. After PSM, the advantage of URY in PFS was verified again, while there was no significant difference in overall survival (OS) between the two groups. Cox multivariate analysis suggested that lower RSS was associated with better PFS.ConclusionsTLTG with URY for GC helps control disease progression, speed up recovery and reduce short and long-term complications, especially RSS.

There has been a steady increase in the incidence of signet ring cell (SRC) carcinoma, a distinct histological type with cells containing abundant intracytoplasmic mucin. We aimed to analyze the clinicopathological characteristics and prognostic value of patients with SRC gastric cancer (GC) who underwent gastrectomy.Clinical data of 10,312 GC patients who underwent D2 radical gastrectomy were obtained from the Surveillance, Epidemiology, and End Results database and were retrospectively analyzed. X-tile plots were constructed to illustrate the optimal cut-off points using the minimum P-value from the log-rank Chi-squared test. The Kaplan–Meier method was used for the analysis of the overall cumulative probability of survival. Their differences were evaluated using the log-rank test. The Cox multiple factors analysis was performed using the logistic regression method.In total, 946 (9.17%) SRC GC patients with pT1a-4bN0-3bM0 stage cancer were recruited. The optimal cut-off point for size was 49 mm. The 3-year overall survival (OS) rates of the SRC GC, large-size, and small-size groups were 35.89%, 30.63%, and 44.96%, respectively (P < .05). Cox multivariate analysis showed that tumor size (odds ratio [OR] = 2.032), T3 category (OR = 1.324), T4a category (OR = 1.945), and T4b category (OR = 2.163) were independent hazard prognostic factors.SRC GC has a distinct biological behavior, presents as a large-sized tumor (≥49 mm), and is associated with worse outcomes. SRC GC patients have 2.032 times risk of mortality. SRC patients with larger tumors are at higher risk for infiltrative growth, lymph node metastasis, and distant metastasis.