Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Laparoscopic radical gastrectomy for gastric cancer: Long-term outcome in a teaching center.

BACKGROUND: Laparoscopic gastrectomy for gastric cancer (GC) are increasing, yet the evidence of the relationship between the learning curve and long-term outcomes is limited. AIMS: To analyze the relationship between the learning curve and survival in GC patients over a 10-year period. METHODS: This retrospective cohort study studied 3674 patients who underwent laparoscopic radical gastrectomy for gastric cancer. Cusum and Cox regression analysis were used to assess the association between the surgeon's experience and the 3 years overall survival (OS). RESULTS: The 3-year OS of all patients was 71.8 %. This increase of 3-year OS was associated with laparoscopic cases (r = 0.638, p = 0.047). Analysis of the CUSUM curve showed a significant change in the 3-year OS of 1400 cases. Further propensity score matching (PSM) of patients during and after the learning curve (<1400 and ≥ 1400 cases) showed a significant difference in the 3-year OS between the two groups (68.5 % vs. 72.3 %, p = 0.045). Cox regression analysis verified that in ≥1400 cases, prior laparoscopic surgery (p = 0.045), textbook outcome (TO) and the number of retrieved lymph nodes (LNs) were independent protective factors. The LN non-compliance rate was an independent risk factor. In contrast, the rate of TO and the median number of retrieved LNs were significantly higher after the learning curve (≥1400 cases). Furthermore, the rates of LN non-compliance were significantly lower (p < 0.05). CONCLUSIONS: Increasing laparoscopic surgical experience is associated with surgical quality and prognostic improvement in patients with gastric cancer. But improvements in outcomes accrued slowly over a long period.

Neurotransmitter Receptor HTR2B Regulates Lipid Metabolism to Inhibit Ferroptosis in Gastric Cancer.

Nerves can support tumor development by secreting neurotransmitters that promote cancer cell proliferation and invasion. 5-Hydroxytryptamine (5-HT) is a critical neurotransmitter in the gastrointestinal nervous system, and 5-HT signaling has been shown to play a role in tumorigenesis. Here, we found that expression of the 5-HT receptor HTR2B was significantly elevated in human gastric adenocarcinoma tissues compared with nontumor tissues, and high HTR2B expression corresponded to shorter patient survival. Both 5-HT and a specific HTR2B agonist enhanced gastric adenocarcinoma cell viability under metabolic stress, reduced cellular and lipid reactive oxygen species, and suppressed ferroptosis; conversely, HTR2B loss or inhibition with a selective HTR2B antagonist yielded the inverse tumor suppressive effects. In a patient-derived xenograft tumor model, HTR2B-positive tumors displayed accelerated growth, which was inhibited by HTR2B antagonists. Single-cell analysis of human gastric adenocarcinoma tissues revealed enrichment of PI3K/Akt/mTOR and fatty acid metabolism-related gene clusters in cells expressing HTR2B compared with HTR2B-negative cells. Mechanistically, HTR2B cooperated with Fyn to directly regulate p85 activity and trigger the PI3K/Akt/mTOR signaling pathway, which led to increased expression of HIF1α and ABCD1 along with decreased levels of lipid peroxidation and ferroptosis. Together, these findings demonstrate that HTR2B activity modulates PI3K/Akt/mTOR signaling to stimulate gastric cancer cell survival and indicate that HTR2B expression could be a potential prognostic biomarker in patients with gastric cancer. SIGNIFICANCE: Nerve cancer cross-talk mediated by HTR2B inhibits lipid peroxidation and ferroptosis in gastric cancer cells and promotes viability under metabolic stress, resulting in increased tumor growth and decreased patient survival.