Evidence suggests that metformin might be a potential candidate for breast cancer treatment. Yet, its relevant molecular mechanisms remain to be fully investigated. We found that metformin could suppress the N6-methyladenosine (m⁶A) level in breast cancer cells significantly. The latter has an essential role in breast cancer progression and is newly considered as a therapeutic target. In this study, we measured the m⁶A level by m⁶A colorimetric analysis and dot blot assay. We then performed qRT-PCR, western blot, MeRIP, dual-luciferase reporter assay, and others to explore the m⁶A-dependent pathway associated with metformin. In vivo effect of metformin was investigated using a mouse tumorigenicity model. In addition, breast cancer and normal tissues were used to determine the role of METTL3 in breast cancer. Metformin could reduce the m⁶A level via decreasing METTL3 expression mediated by miR-483-3p in breast cancer. METTL3 is known to be able to promote breast cancer cell proliferation by regulating the p21 expression by an m⁶A-dependent manner. Metformin can take p21 as the main target to inhibit such effect. To specify, this study exhibited that metformin can inhibit breast cancer cell proliferation through the pathway miR-483-3p/METTL3/m⁶A/p21. Our findings suggest that METTL3 may be considered as a potential therapeutic target of metformin for breast cancer.

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is abundantly expressed in a variety of cancer cells, including lung cancer cells, resulting in low sensitivity of these cells to various apoptotic stimuli; Cisplatin (CDDP), a commonly used chemotherapeutic agent of several cancers, has a major limitation because of its toxicity at high concentration. In the present study, we constructed a plasmid encoding Survivin shRNA to knockdown survivin with low dose DDP both in vitro and in vivo. The specificity and potency of the shRNA were validated by western blot, flow cytometric and MTT in H292 lung cancers cells. In vivo, therapy experiments were conducted on nude mice bearing H292 xenograft tumors. The Survivin shRNA expression plasmid was administered systemically in combination with low-dose CDDP on a frequent basis. Assessments of angiogenesis, cell proliferation and apoptosis were performed by using immunohistochemistry against CD31, Ki67 and TUNEL assays, respectively. The results revealed that treatment with the Survivin shRNA plus low-dose CDDP reduced volume by approximately 83.13% compared with the blank control (P < 0.01), accompanied with angiogenesis inhibition (p < 0.01), tumor cell proliferation suppression (p < 0.05) and apoptosis induction (p < 0.01). Moreover, combination treatment also significantly reduced the mean tumor volume compared with other treatment alone (p < 0.05). Taken together, our study suggested that silencing of survivin sensitized H292 lung cancer cells to chemotherapy of CDDP, suggesting potential applications of the combined approach in the treatment of lung cancer.

Background: Metabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear. Methods: Genomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings. Results: A total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer. Conclusion: This study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Background: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. Methods: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. Results: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors—including smoking, alcohol consumption, major depression, and body mass index (BMI)—these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14–1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03–1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19–1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22–2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23–5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. Conclusions: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.

Invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) account for most cases of breast cancer. However, there is ongoing debate about any potential variations in overall survival (OS) between ILC and IDC. This study aimed to compare survival between IDC and ILC, identify prognostic factors for ILC patients, and construct a nomogram for predicting OS rates. This retrospective cohort analysis utilized data from the Surveillance, Epidemiology, and End Results (SEER) Cancer Database. Patients diagnosed with ILC and IDC between 2000 and 2019 were enrolled. To minimize baseline differences in clinicopathological characteristics and survival outcomes, a propensity score matching (PSM) method was used. Data from the multivariate Cox regression analyses were used to construct a predictive nomogram for OS at 1, 3, and 5 years, incorporating all independent prognostic factors. Following the PSM procedure, patients with ILC exhibited a better prognosis compared to those with IDC. TNM stage, age >70, radiotherapy, surgery, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HR-/HER2+) subtype were identified as independent factors for OS in ILC patients. Surgery and radiotherapy effectively reduced the risk of death, while chemotherapy did not demonstrate the same benefit. This model could support clinicians in evaluating the prognosis of ILC for decision-making and patient counseling.