PI3K/AKT/mTOR pathway mediated‐cell cycle dysregulation contribute to malignant proliferation of mouse spermatogonia induced by microcystin‐leucine arginine

Abstract

Environmental cyanotoxin exposure may be a trigger of testicular cancer. Activation of PI3K/AKT/mTOR signaling pathway is the critical molecular event in testicular carcinogenesis. As a widespread cyanotoxin, microcystin-leucine arginine (MC-LR) is known to induce cell malignant transformation and tumorigenesis. However, the effects of MC-LR on the regulatory mechanism of PI3K/AKT/mTOR pathway in seminoma, the most common testicular tumor, are unknown. In this study, mouse spermatogonia cell line (GC-1) and nude mice were used to investigate the effects and mechanisms of MC-LR on the malignant transformation of spermatogonia by nude mouse tumorigenesis assay, cell migration invasion assay, western blot, and cell cycle assay, and so forth. The results showed that, after continuous exposure to environmentally relevant concentrations of MC-LR (20 nM) for 35 generations, the proliferation, migration, and invasion abilities of GC-1 cells were increased by 120%, 340%, and 370%, respectively. In nude mice, MC-LR-treated GC-1 cells formed tumors with significantly greater volume (0.998 ± 0.768 cm 3 ) and weight (0.637 ± 0.406 g) than the control group (0.067 ± 0.039 cm 3 ; 0.094 ± 0.087 g) (P < .05). Furthermore, PI3K inhibitor Wortmannin inhibited the PI3K/AKT/mTOR pathway and its downstream proteins (c-MYC, CDK4, CCND1, and MMP14) activated by MC-LR.Blocking PI3K alleviated MC-LR-induced cell cycle disorder and malignant proliferation, migration and invasive of GC-1 cells. Altogether, our findings suggest that MC-LR can induce malignant transformation of mouse spermatogonia, and the PI3K/ AKT/mTOR pathway-mediated cell cycle dysregulation may be an important target for malignant proliferation. This study provides clues to further reveal the etiology and pathogenesis of seminoma.

Downregulation of LncRNA GCLC-1 Promotes Microcystin-LR-Induced Malignant Transformation of Human Liver Cells by Regulating GCLC Expression

“…The 25th passage of sh-lncGCLC-transfected cells, vector-transfected cells, and control cells (with or without MCLR treatment) were harvested after adjusting the cell suspension to 1 × 10 7 /mL with PBS, then, 100 μL was injected subcutaneously into nude mice to evaluate the tumorigenicity of transformed cells. The tumor volume was measured every three days and calculated using the equation: V = (LW 2 )/2 (L, longitudinal diameter; W, width diameter) [ 25 , 27 ]. After 22 days of injection, the mice were sacrificed, and tumors were harvested, weighed, and fixed with 4% paraformaldehyde for pathological examination.…”

Circular RNA nuclear receptor interacting protein 1 promoted biliary tract cancer epithelial‐mesenchymal transition and stemness by regulating the miR‐515‐5p/AKT2 axis and PI3K/AKT/mTOR signaling pathway

“…They achieve these effects by binding to target mRNAs, leading to the inhibition or degradation of mRNA translation 28 . The PI3K/AKT/mTOR signaling pathway, one of the most frequently dysregulated pathways in human cancers, governed key processes such as metabolism, differentiation, and proliferation, which were crucial for the survival, expansion, and dissemination of cancer cells 30–32 …”

“…28 The PI3K/AKT/mTOR signaling pathway, one of the most frequently dysregulated pathways in human cancers, governed key processes such as metabolism, differentiation, and proliferation, which were crucial for the survival, expansion, and dissemination of cancer cells. [30][31][32] This research first elucidated that circ_NRIP1 was overexpressed in BTC and intimately correlated to gloomy prognosis. Moreover, the aberrant expression of circ_NRIP1 boosted tumor proliferation, metastasis, epithelial-mesenchymal transition (EMT) and stemness maintenance in vitro and in vivo.…”