Background: C677T polymorphism of the methylenetetrahydrofolate reductase ( MTHFR ) has been associated with recurrent pregnancy loss (RPL). However, results were conflicting. The aim of this study was to quantitatively summarize the evidence for MTHFR C677T polymorphism and RPL risk. Methods: Electronic search of PubMed and the Chinese Biomedicine database was conducted to select studies. Case-control studies containing available genotype frequencies of C677T were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. Results: The case-control studies including 2427 cases and 3118 controls were identified. The meta-analysis stratified by ethnicity showed that individuals with the homozygous TT genotype had increased risk of RPL (OR=1.574, 95% CI: 1.163-2.13, p =0.003), in Asians (OR=1.663, 95% CI: 1.012-2.731, p =0.045). Results among Caucasians did not suggest an association (OR=1.269, 95% CI: 0.914-1.761, p =0.155). A symmetric funnel plot, the Egger's test ( p =0.285), and the Begg's test ( p =0.529) were all suggestive of the lack of publication bias. The studies conducted in each of the defined number of pregnancy losses—two or more pregnancy losses, and three or more pregnancy losses—showed no effect of the C677T polymorphism on RPL except for the TT versus CT+CT genotype comparison for the three or more pregnancy loss subgroup (OR=1.792, 95% CI: 1.187-2.704, p =0.005). Conclusion: This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk of RPL, except for Caucasians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between MTHFR C677T polymorphism and RPL.

The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy.

Background: Cancer-associated fibroblasts (CAFs) play important roles in cancer development and progression. Recent studies show that p53 plays a cell non-autonomous tumor-suppressive role to restrict tumor growth in CAFs. However, the role of p53 mutant in CAFs remains obscure. Methods: In this study, the contribution of p53 mutant p53^N236S (p53S) to CAFs activation was examined using mouse embryonic fibroblasts (MEFs) from wild-type (WT), p53 deficient (p53^-/-) and p53^S/S mice. The role of p53S in MEFs in inducing prostate cancer cell growth and metastasis was studied by utilizing xenograft models and transwell assays. The effects of p53S on the properties of CAFs were assessed by measuring CAFs-specific factors expression and functional collagen contraction assay. Moreover, Microarray data were analyzed by GSEA and Stat3 signaling was inhibited to further determine p53S’s role in the CAFs activation. Results: We found that p53^S/S MEF accelerated cancer cells growth and metastasis compared with WT and p53^-/- MEF. We also found that p53S induced significantly increasing collagen contraction in fibroblasts and overexpression of CAFs-specific factors, such as α-smooth muscle actin (α-SMA), FGF10 and CXCL12. p53S regulated these CAF-specific properties through Stat3 activation. Conclusion: Our results illustrate that p53S plays an important role in CAFs activation by the Stat3 pathway. The study indicates that cancer cells and fibroblasts interaction promotes prostate cancer cell growth, migration and invasion due to p53S expression in fibroblasts.

Aging has been recently reported to promote lung cancer initiation and progression. Senescent fibroblasts gain a cancer-associated fibroblast (CAF) phenotype, and exert a powerful influence on cancer behavior, such as tumor cell growth and metastasis. However, mechanisms linking fibroblast senescence with CAF activation remain poorly understood. Our study shows that senescent fibroblasts displayed CAF properties, including the highly expressed CAF markers, α-SMA and Vimentin, and CAF-specific factors, CXCL12, FGF10, IL6 and COL1A1, which significantly increased collagen contractile activity and promoted the migration and invasion of lung cancer cells, H1299 and A549. We were further able to show that CAF characteristics in senescent fibroblasts could be regulated by the Stat3 pathway. Intracellular ROS accumulation activates the Stat3 pathway during senescence. Thus, our findings indicate that senescent fibroblasts mediate a CAF function with the Stat3 pathway. We further propose a novel Stat3 dependent targetable mechanism, which is instrumental in mediating the migration and invasion of lung cancer cells.