Osteoporosis is a common metabolic bone disease, influenced by genetic and environmental factors, that increases bone fragility and fracture risk and, therefore, has a serious adverse effect on the quality of life of patients. However, epigenetic mechanisms involved in the development of osteoporosis remain unclear. There is accumulating evidence that epigenetic modifications may represent mechanisms underlying the links of genetic and environmental factors with increased risk of osteoporosis and bone fracture. Some RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been shown to be epigenetic regulators with significant involvement in the control of gene expression, affecting multiple biological processes, including bone metabolism. This review summarizes the results of recent studies on the mechanisms of miRNA-, lncRNA-, and circRNA-mediated osteoporosis associated with osteoblasts and osteoclasts. Deeper insights into the roles of these three classes of RNA in osteoporosis could provide unique opportunities for developing novel diagnostic and therapeutic approaches to this disease.

Background. The tumor-infiltrating immune cells are closely associated with the prognosis of gastric cancer (GC). This article is aimed at determining the composition change of immune cells and immune regulatory factors in GC and normal tissues, depicting their prognosis value in GC, and revealing the relationship between them and GC clinical parameters. Methods. We used CIBERSORT to calculate the proportion of 22 immune cells in the GC or normal tissues; a t -test was applied to assess the expression difference of immune cells and immune regulatory factors in normal and GC tissues. The relationship of the immune cells, immune regulatory factors, and GC patients’ clinical characteristics was assessed by univariate analysis. Results. In this study, we found that the proportion of macrophages increased, while plasma cells and monocytes decreased in GC tissues. In these immune fractions, Tregs and naïve B cells were found to be correlated with GC patients’ prognosis. Interestingly, the expression of immune regulatory factors was ambiguous with their classical function in GC tissues. For example, TIM-3, FOXP3, and CMTM6 were overexpressed, while CD27 and PD-1 were underexpressed in GC tissues. We also found that IDO1, PD-1, TIGIT, and TIM-3 were highly expressed in high-grade GC tissues, the HERC2 expression level was related to patients’ gender, and the TIGIT expression level was sensitive to targeted therapy. Furthermore, our results suggested that the infiltration of Tregs and naive B cells was strongly correlated with the T stage, radiation therapy, targeted molecular therapy, and the expression levels of TIM-3 and FOXP3 in GC. Conclusion. The expression pattern of tumor-infiltrating immune cells and immune regulatory factors was systematically depicted in the GC tumor microenvironment, indicating that individualized treatment based on the tumor-infiltrating immune cells and immune regulatory factors may be beneficial to GC patients.

In this study, we have undertaken the whole proteomic analysis and got a better understanding of biological processes involved in the development and progression of ccRCC. We hope promising biomarkers can be uncovered to facilitate early diagnosis, predict the prognosis and progression, more importantly, to be applied as potential therapeutic targets. Experimental design: Fresh frozen tissue samples were surgically resected from patients with local or locally advanced ccRCC. Trypsin digested proteins were analyzed using TMT-based LC-MS/MS proteomic approach, followed by bioinformatic analysis. A potential prognostic marker FMNL1 was chosen to be validated in TCGA_KIRC datasets (n=525 and 72), further validation sets (n=10 and 10) and expanded validation sets (n=81 and 16). The effects of FMNL1 on proliferation, migration and invasion were determined by colony formation, wound healing, and transwell assays in 786-O and Caki-1 cells in vitro study. Results: A total of 657 differentially expressed proteins were identified and quantified between ccRCC and adjacent normal tissues (p-value<0.05, FC>2 or<1/2), of which 186 proteins were up-regulated and 471 proteins were down-regulated. Bioinformatic analysis showed enriched metabolic biological processes and pathways. Univariate and multivariate analysis defined FMNL1 as an independent negative prognostic marker in the TCGA datasets. High expression of FMNL1 correlated significantly with tumor stage and distant metastasis (P<0.05) both in the TCGA-KIRC datasets and expanded validation sets. Kaplan-Meier survival curve illustrated that the patients with high FMNL1 protein level had shorter OS time in the expanded validation sets (p=0.0273). In vitro experiments presented the functional effects of FMNL1 knockdown on the inhibition of proliferation, migration and invasion in cancer cell lines. Conclusion and clinical relevance:The proteomic results uncovered sophisticated metabolic reprogramming of ccRCC and indicated that the upregulation of rate-limiting enzymes in glycolysis and mitochondrial impairment may be the cause of metabolic reprogramming in ccRCC. Moreover, FMNL1 has been identified as a promising prognostic marker, and knockdown of FMNL1 could inhibit ccRCC cell proliferation, migration and invasion, which might be used as a new effective therapeutic strategy to inhibit the progression of ccRCC.

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