MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Forkhead box transcription factor, FOXM1 is implicated in several cellular processes such as proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis, apoptosis, and redox signaling. In addition to being a boon for the normal functioning of a cell, FOXM1 turns out to be a bane by manifesting in several disease scenarios including cancer. It has been given an oncogenic status based on several evidences indicating its role in tumor development and progression. FOXM1 is highly expressed in several cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in angiogenesis, invasion, migration, self- renewal and drug resistance. In this review, we attempt to understand various mechanisms underlying FOXM1 gene and protein regulation in cancer including the different signaling pathways, post-transcriptional and post-translational modifications. Identifying crucial molecules associated with these processes can aid in the development of potential pharmacological approaches to curb FOXM1 mediated tumorigenesis.

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FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis.

Background: Gastric cancer (GC) is one of the main mortality cause worldwide. Previously, we found Forkhead box protein (FOXM1) or Urokinase-type plasminogen activator (PLAU) are independent prognostic markers of GC. This study aims to explore the combining prognostic efficacy and the potential insights underlying additive effect of FOXM1 to PLAU in GC progression through in-silico analyses. Method: The expression of FOXM1 and PLAU were profiled in 33 cancer types using public data. A merged GC expression dataset containing 598 samples was used for evaluating prognostic significance of FOXM1/PLAU. Gene Set Enrichment Analysis (GSEA) was performed to elucidate the mechanisms underlying FOXM1/PLAU promoted GC progression. The Cancer Genome Atlas (TCGA) was used for analyzing the association between FOXM1/PLAU and tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were also computed using TCGA GC data. Drugs targeting FOXM1/PLAU associated gene expression pattern was analyzed using LINCs database. Results: FOXM1 and PLAU are overexpressed in 17/33 cancer types including GC. Kaplan-Meier analyses indicate that the FOXM1+PLAU+ subgroup have the worst prognosis, while FOXM1-PLAU- subgroup have the best survival. Bioinformatics analysis indicated that FOXM1+PLAU+ associated genes are enriched in TGF-beta, DNA repair and drug resistance signaling pathways; FOXM1 and PLAU expression are negatively correlated with tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were presented. Data mining from LINCs suggested several chemicals or drugs that could target the gene expression pattern of FOXM1+PLAU+ patients. Conclusion: FOXM1+PLAU+ can serve as effective prognostic biomarkers and potential therapeutic targets for GC. Due to the additive effect of these two genes, screening for drugs or chemicals that targeting the expression patterns PLAU+FOXM1+ subgroup may exert important clinical impact on GC management.

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FOXM1 functions collaboratively with PLAU to promote gastric cancer progression.

Renal cell carcinoma (RCC) is a most common type of urologic neoplasms; it accounts for 3% of malignant tumors, with high rates of relapse and mortality. The most common types of renal cancer are clear cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal carcinoma (chRCC), which account for 90%, 6-15%, and 2-5%, respectively, of all renal malignancies. Although surgical resection, chemotherapy, and radiotherapy are the most common treatment method for those diseases, their effects remain dissatisfactory. Furthermore, recent research shows that the treatment efficacy of checkpoint inhibitors in advanced RCC patients is widely variable. Hence, patients urgently need a new molecular biomarker for early diagnosis and evaluating the prognosis of RCC. MicroRNAs (miRNAs) belong to a family of short, non-coding RNAs that are highly conserved, have long half-life evolution, and post-transcriptionally regulate gene expression; they have been predicted to play crucial roles in tumor metastasis, invasion, angiogenesis, proliferation, apoptosis, epithelial-mesenchymal transition, differentiation, metabolism, cancer occurrence, and treatment resistance. Although some previous papers demonstrated that miRNAs play vital roles in renal cancer, such as pathogenesis, diagnosis, and prognosis, the roles of miRNAs in kidney cancer are still unclear. Therefore, we reviewed studies indexed in PubMed from 2017 to 2020, and found several studies suggesting that there are more than 82 miRNAs involved in renal cancers. The present review describes the current status of miRNAs in RCC and their roles in progression, diagnosis, therapy targeting, and prognosis of RCC.

A Review of Recent Research on the Role of MicroRNAs in Renal Cancer.

Saroglitazar attenuates renal fibrosis induced by unilateral ureteral obstruction via inhibiting TGF-β/Smad signaling pathway.

Pyroptosis, a newly identified type of lytic programmed cell death (PCD), is featured in pore formation in the plasma membrane, swelling, and cell rupture with secretion of cellular contents, especially the inflammatory cytokines. A large number of studies have shown that pyroptosis includes not only the GSDMD involved caspase-1-dependent classical pathway and caspase-11/4/5-dependent non-classical pathway, but also the GSDME involved caspase-3 (Casp3) dependent pathway. Diabetic nephropathy (DN) is one of the most serious microvascular complications in diabetes. Present evidence suggestes that pyroptosis promotes the progression of several diabetic complications including DN. The underlying mechanism mediating renoprotection conferred by GSDME regulation in the diabetic kidney, specifically in human tubular cells has been investigated. Z-DEVD-FMK, the inhibitor of Casp3, ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVDFMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stimulated HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Based on this, it is not difficult to conclude that therapies targeting Casp3/GSDME dependent pyroptosis show great application prospects in DN, and novel nephroprotective strategy using GSDME-derived peptides directed against Casp3-induced cell death in vitro and in vivo may be a key breakthrough for this goal. Therefore, in the mini-review, we introduced the history of pyroptosis; gasdermin family proteins especially GSDME, and GSDME mediated pyroptosis in DN, expecting this novel mechanism may provide valuable therapeutic insights for the treatment of DN.

Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy

An increasing body of evidence has indicated that microRNAs (miRNAs/miRs) may play an important role in tumourigenesis and tumour progression. Recent studies have demonstrated that miR-320a is aberrantly expressed in a variety of different types of human cancer. The results of the present study confirmed that the expression of miR-320a was decreased in clinical specimens and cell lines. Expression of miR-320a inhibited the growth and invasive ability of ACHN and Caki-1 cells. Bioinformatics analysis and a luciferase reporter assay demonstrated that forkhead box protein M1 (FoxM1) was directly regulated by miR-320a. Rescue experiments in vitro revealed that the upregulation of FoxM1 antagonized the miR-320a-mediated malignant phenotype in renal cancer. Furthermore, experiments employing a xenograft mouse model revealed that the upregulation of miR-320a inhibited the proliferation of renal cancer cells in nude mice when FoxM1 protein expression was reduced. Collectively, the present study demonstrated a novel molecular interaction regulated by miR-320a, which may provide a novel insight into the treatments for renal cancer.

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MicroRNA‑320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) patients who progress to end-stage renal disease (ESRD). With the increasing incidence of CKD, it is of importance to...

Wen Li

Papers

Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy

MicroRNA‑320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1

FFNT25 ameliorates unilateral ureteral obstruction-induced renal fibrosis.