ABSTRACT
Background: Gastric cancer (GC) is a malignant form of cancer that severely threatens human health. Despite developments on treatment, the prognosis of patients with advanced GC remains poor. Hence, the identification of detailed molecular mechanisms and potential therapeutic targets is of great importance for GC study. In recent years, circular RNAs have been widely reported to be important regulators in cancer initiation and progression. This study sought to evaluate the function of circRHOT1 in GC development. Methods: Clinical specimens were collected from patients with GC to detect the level of circRHOT1. The expression of circRHOT1 in several GC cell lines was detected by quantitative real-time polymerase chain reaction. Cell Counting Kit 8 (CCK-8), colony formation, and xenograft tumor growth experiments were performed to check cell proliferation. Cell ferroptosis was determined by the levels of intracellular iron, Fe2+ (Divalent iron ion), lipid reactive oxygen species, malondialdehyde, and glutathione. The protein levels of SLC7A11 and glutathione peroxidase-4 (GPX4) were detected by western blot assays. The epigenetic regulation of the GPX4 gene was analyzed by chromatin immunoprecipitation assays. Results: CircRHOT1 was more highly expressed in the GC tumors than the adjacent non-tumor tissues. The knockdown of circRHOT1 significantly suppressed cell growth (P<0.05) and stimulated the ferroptosis of the GC cells (P<0.05). CircRHOT1 recruited KAT5 (Acetyltransferase Tip60) to promote the acetylation of lysine 27 on histone H3 protein subunit (H3k27Ac) of the GPX4 gene and stimulated gene transcription. The overexpression of KAT5 and GPX4 notably reversed the anti-proliferation effect of circRHOT1 depletion (P<0.05). Conclusions: CircRHOT1 promoted GC progression and suppressed ferroptosis by recruiting KAT5 to initiate GPX4 transcription. Our findings showed that cirRHOT1 is a promising target for GC treatment.
ABSTRACT
Background: 5-Fluorouracil and its oral prodrug, capecitabine, are frequently used in the treatment of gastrointestinal cancers-including gastric cancer-but carry a cardiotoxicity risk. Raltitrexed (brand name Tomudex), a direct inhibitor of thymidylate synthase, has been successfully used as an alternative to fluoropyrimidines in patients with 5-fluorouracil-induced cardiac events. We report the first case, to our knowledge, of raltitrexed used with trastuzumab and platinum-based chemotherapy as a substitute for fluoropyrimidines following cardiotoxicity in a 78-year-old male patient with metastatic gastric cancer. Case Description: The patient experienced a myocardial infarction 3 days after beginning treatment with capecitabine, carboplatin, and trastuzumab for metastatic HER2+ gastric adenocarcinoma. Capecitabine was replaced with raltitrexed, and the patient ultimately received seven cycles of chemotherapy, five of which included raltitrexed. There were no cardiotoxic events attributable to raltitrexed, although the patient did experience hypotensive episodes, premature ventricular contractions, myelosuppression, and anemia. Progression-free survival was 4.5 months, within the expected range achieved with the ToGA regimen (trastuzumab, cisplatin, 5-fluorouracil chemotherapy). At time of writing, the patient has been alive for 48 weeks since diagnosis. Conclusions: In summary, raltitrexed appears to be a safe alternative to fluoropyrimidines when combined with trastuzumab and platinum, although more data is needed to determine its relative effectiveness.
