The overall prognosis of advanced/metastatic gastric cancer (GC) remains poor despite the development of pharmacotherapy. Therefore, other treatment options, such as complementary and alternative medicine, should be considered to overcome this aggressive malignancy. Andrographis, which is a generally unharmful botanical compound, has gained increasing interest for its anticancer effects in multiple malignancies via the regulation of cancer progression-associated signaling pathways. In the present study, a series of in vitro experiments (cell proliferation, colony formation and apoptosis assays) was designed to elucidate the antitumor potential and mechanism of Andrographis in GC cells. The present study demonstrated that Andrographis exerted antitumor effects in GC cell lines (MKN74 and NUGC4) by inhibiting proliferation, reducing colony formation and enhancing apoptotic activity. Furthermore, it was demonstrated that the expression levels of the ferroptosis-associated genes heme oxygenase-1, glutamate-cysteine ligase catalytic and glutamate-cysteine ligase modifier were significantly upregulated after Andrographis treatment in both GC cell lines in reverse transcription-quantitative PCR experiments (P<0.05); this finding was further confirmed by immunoblotting assays (P<0.05). In conclusion, to the best of our knowledge, the present study was the first to demonstrate that Andrographis possessed antitumor properties by altering the expression levels of ferroptosis-associated genes, thereby providing novel insights into the potential of Andrographis as an adjunctive treatment option for patients with metastatic GC.
Methyltransferase-like 3 (METTL3) is a crucial component of the m6A methyltransferase complex, which serves pivotal roles in tumor progression. The present study investigated the prognostic significance of METTL3 expression in gastric cancer (GC). The expression levels of METTL3 were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissue specimens from 158 patients with GC. Propensity score matching (PSM) analysis was performed to clarify its prognostic potential. METTL3 gene expression was also investigated in fresh frozen specimens from another independent cohort of 57 patients with GC to establish its clinical relevance. Knockdown of METTL3 by small interfering RNA transfection was performed to evaluate its function in vitro. METTL3 expression was significantly higher in cancerous tissues compared with in corresponding normal mucosa (P<0.0001), and high METTL3 expression was an independent prognostic factor for overall and disease-free survival in the FFPE cohort of patients with GC. PSM analysis revealed that elevated METTL3 expression was significantly associated with poor survival outcomes, which was subsequently validated in another cohort of fresh frozen specimens. Knockdown of METTL3 inhibited proliferation, invasion, migration and anoikis resistance in GC cells. In conclusion, METTL3 expression may be used as a clinically feasible prognostic marker and could serve as a potential therapeutic target in patients with GC.
Background: Gastric cancer (GC) is one of the most common cancers and leading cause of cancer-related deaths worldwide, primarily because of rapid disease progression to advanced stages and highly malignant potential. Methyltransferase-like 3 (METTL3) is a crucial component of the m6A methyltransferase complex, and plays pivotal roles in tumour progression. This study investigated the prognostic significance of METTL3 expression in gastric cancer (GC). Methods: We assessed expression levels of METTL3 by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissue specimens from one hundred fifty-eight GC patients. Propensity score matching (PSM) analysis was performed to clarify its prognostic potential. The METTL3 gene expression was also investigated in fresh frozen specimens from another independent cohort of fifty-seven GC patients to establish its clinical relevance. Knockdown of METTL3 by siRNA transfection was performed to evaluate its function in vitro. Results: METTL3 expression was significantly higher in cancerous tissues vs. corresponding normal mucosa (P<0.0001), and high METTL3 staining group was significantly associated with males (P=0.029), an advanced T stage (P=0.0002), the presence of venous invasion (P<0.0001), lymphatic vessel invasion (P=0.011), lymph node metastasis (P=0.004), distant metastasis (P=0.0004), and advanced TNM stage classification (P=0.0001) in the FFPE cohort of GC patients. Survival curve analysis showed that patients with increased expression of METTL3 showed poorer prognosis in terms of both overall survival (OS: P<0.0001, log-rank test) and disease-free survival (DFS: P=0.0005, log-rank test) compared to those with low expression. Multivariate analysis revealed that increased expression of METTL3 was an independent prognostic factor for overall survival (OS: hazard ratio (HR), 3.24; 95% confidence interval (CI), 1.57-6.68; p=0.001) and disease-free survival (DFS: HR, 2.4; 95% CI, 1.12-5.16; p=0.025) in the FFPE cohort of GC patients. PSM analysis revealed that elevated METTL3 expression was significantly associated with poor survival outcomes (OS: P=0.05; DFS: P=0.038; log-rank test), which was subsequently validated in another cohort of fresh frozen specimens (OS: p=0.007; DFS: p=0.029; log-rank test). The knockdown of METTL3 inhibited proliferation, invasion, migration, and anoikis resistance in GC cells. Conclusion: METTL3 expression may be used as a clinically feasible prognostic marker and could serve as a potential therapeutic target in GC patients. Citation Format: Yoshinaga Okugawa, Yuji Toiyama, Chengzeng Yin, Ma Ruiya, Akul Goel, Takashi Ichikawa, Hiroki Imaoka, Takahito Kitajima, Tadanobu Shimura, Mikio Kawamura, Hiromi Yasuda, Hiroyuki Fujikawa, Takeshi Yokoe, Ikuyo Mochiki, Masaki Ohi, Kaname Nakatani. Clinical value and oncogenic role of METTL3 expression in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 653.
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