Metformin regulates autophagy via LGMN to inhibit choriocarcinoma.

Choriocarcinoma has the problem of chemotherapy insensitivity and recurrence. Metformin may be a promising candidate to restrict choriocarcinoma progress because of its indirect and direct beneficial role on inhabitations of cancer cells without severe adverse side effects. In this study, metformin pressed the proliferation and invasion of choriocarcinoma JAR cells in vitro and the growth of the JAR subcutaneous xenografts in vivo. The high throughput sequencing and bioinformatics technology identified the low expression of legumain (LGMN) in lysosomal pathway caused by metformin, which was upregulated in human choriocarcinoma tissues compared with the early pregnancy tissues. As elevating metformin concentration and treatment time, the mRNA and protein expression of LGMN both depressed in two choriocarcinoma cell lines (JAR and JEG-3). LGMN was involved in metformin-mediated inhibition of cell proliferation and invasion. Furthermore, metformin induced autophagy via inhibiting LGMN through AKT/mTOR/LC3II signaling pathway of choriocarcinoma. Autophagy inhibitor could depress metformin-induced autophagy and improve cell proliferation and invasion ability dropped by metformin, while autophagy inducer could partially reverse the change of cell proliferation and invasion modulated by combination of metformin and LGMN overexpression. These results indicated that metformin inhibited cell proliferation and invasion ability by inducing autophagy in a LGMN-dependent manner so as to play a role in the treatment of choriocarcinoma.

Association between Peripheral CD19+ B Cells and Reproductive Outcome in Women with Recurrent Implantation Failure.

BACKGROUND: To investigate the roles of T, B, and natural killer (NK) cells in pregnancy outcome of women with recurrent implantation failure (RIF). METHODS: This retrospective cohort study enrolled 196 patients with RIF. Peripheral lymphocyte subsets were measured before and during pregnancy. The relationship between pregnancy outcome and level of lymphocytes was analyzed. RESULTS: Peripheral CD19+ B cells in women who experienced miscarriage were significantly lower than those who subsequently had live birth. After adjusting for potential confounders in the multiple logistic regression models, each 1% increment in the peripheral CD19+ B cells before pregnancy [odds ratio (OR): 0.93] and during early pregnancy (OR: 0.83) was associated with a significantly decreased risk of miscarriage (p < 0.05). The risk of mis-carriage in patients with ≥ 15% CD19+ B cells before and during pregnancy was 39% and 21% lower, respectively, than in their counterparts with < 15% CD19+ B cells. The association between CD19+ B cells and the risk of miscarriage was nonlinear. CONCLUSIONS: Measurement of peripheral CD19+ subsets may help predict the pregnancy outcome in women with RIF.

Insulin resistance in patients with recurrent pregnancy loss is associated with lymphocyte population aberration.

This study was designed to investigate the relationship of insulin resistance (IR) and cellular immune abnormalities associated with women with recurrent pregnancy loss (RPL). Women with RPL were divided into two groups according to their homeostasis model assessment for IR (HOMA-IR) scores. The IR group received metformin approximately 3 months before pregnancy. The percentage of lymphocyte subsets and other blood biochemical indices were tested. The HOMA-IR and fasting serum insulin levels were related to the percentage of lymphocyte subsets. The women with RPL had higher CD3+ and CD3+CD4+ cell levels while CD56+CD16+cell levels were lower. A higher likelihood of cellular immune abnormalities was observed. Women with normal lymphocyte subsets had normal pregnancy outcomes. Metformin significantly downregulated CD3+ and CD3+CD4+ cells and improved pregnancy outcomes. IR was associated with cellular immune abnormalities in RPL. The data suggests that metformin affected the immune/inflammatory response, which may regulate the cellular immune balance and improve pregnancy outcomes. Abbreviations RPL: recurrent pregnancy loss; IR insulin resistance; HOMA-IR: homeostasis model assessment for IR.