Fig 2: Atorvastatin disrupts the Kras/PI3K or Kras/Raf complex and subsequently inhibits the AKT or ERK activation in NSCLC cells. (a) A549 cells and their PIK3CA and PTEN mutants were respectively treated with 1 µM atorvastatin according to specific time points. Lysates were immunoprecipitated by using anti-Kras antibody and analyzed for coimmunoprecipitating p110a or flag antibody using western blotting. AKT activity is represented as the levels of phosphorylated forms of AKT compared with total AKT. (b) Dose response of atorvastatin on the Kras/ p110a complex in A549 cells and their PIK3CA and PTEN mutants. (c) A549 cells were respectively treated with 1 µM atorvastatin according to specific time points. Lysates were immunoprecipitated by using anti-Kras antibody and analyzed for coimmunoprecipitating with Raf antibody. ERK activity was represented as the levels of phosphorylated forms of ERK compared with total ERK. (d) A549 cells and their PIK3CA and PTEN mutants were respectively treated with 5 µM atorvastatin according to specific time points. The protocols of immunoprecipitation and western blotting were similar to those used above. (e) A549 cells were respectively treated with 1 µM or 5 µM atorvastatin for 48 h. Administration with 100 µM mevalonate reversed the inhibitory effect of atorvastatin on the formation of Kras/PI3K or Kras/Raf complex and the activation of AKT and ERK

Fig 3: METTL14 inhibits STAD growth and metastasis in vivo. (A) The representative tumors of METTL14 overexpression or negative control HGC-27 cell after transplanting in nude mice. (B) Comparison of tumor volumes of transplanted tumor nude mice between METTL14 overexpression or negative HGC-27 cells. (C) Comparison of metastasis foci in liver of STAD liver metastasis orthotopic tumor models between METTL14 overexpression or negative HGC-27 cells. (D) The representative pictures of HE-stained, Ki67, PTEN and METTL14 expression in STAD subcutaneous xeno transplantation model. (E) The representative pictures of HE-stained, Ki67, PTEN and METTL14 expression in liver metastasis sites of STAD tumor in orthotopic tumor models. (**P < 0.01; ***P < 0.001).

Fig 4: Model of promoter methylation-mediated SALL2 reduction confers tamoxifen resistance in ER+ breast cancerIn SALL2-hypomethylated ER+ breast cancer, SALL2 activates ER signaling via transcriptional upregulation of ESR1 and inhibits Akt/mTOR signaling via transcriptional upregulation of PTEN (left), leading to an estrogen-dependent growth and tamoxifen sensitivity. In SALL2-hypermethylated ER+ breast cancer, promoter methylation-mediated SALL2 reduction represses ERa and PTEN expression and activates Akt/mTOR signaling, resulting in estrogen-independent tumor growth and tamoxifen-resistant phenotype. DNMT inhibitor-induced SALL2 restoration resensitizes tamoxifen-resistant breast cancer to endocrine therapy (right).

Fig 5: Myeloid cell-specific PTEN deficiency is critical for the induction of Tregs in acute lung injury. Mice were given rHMGB1 at 24 h prior to lung tissue, blood, and cell harvest. (A) The protein was isolated from peritoneal macrophages in PTENflox and PTENM-KO mice after rHMGB1 treatment. The expression of PTEN, p-PDK1, p-Akt (ser473), and ß-catenin was analyzed by Western blots. Representative of three experiments. (B) The density ratio of p-PDK1, and p-Akt (ser473), and ß-catenin. *p < 0.05, **p < 0.01. (C) ELISA-based detection of TGF-ß levels in serum from PTENflox and PTENM-KO mice after rHMGB1 treatment. Mean ± SD (n = 4–6 samples/group), **p < 0.01. (D) Representative diagrams of CD4+CD25+Foxp3+ Tregs in the peripheral blood from PTENflox and PTENM-KO mice after rHMGB1 treatment was analyzed by flow cytometry. (E) The percentage of CD4+CD25+Foxp3+ Tregs in the peripheral blood from PTENflox and PTENM-KO mice after rHMGB1 treatment (n = 4–6 animals/group), Mean±SD, *p < 0.05. (F) q-PCR analysis of mRNA expression coding for Foxp3 in peripheral blood T cells from PTENflox and PTENM-KO mice after rHMGB1 treatment. Mean ± SD (n = 4–6 samples/group), **p < 0.01.