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

Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

/pdf/role-of-pi3k-akt-pathway-in-cancer-the-framework-of-3f2u6pm7nk.pdf

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior.

miRNA profile in ovarian cancer.

The effectual clinical benefits of immune checkpoint inhibitor (ICI) are hampered by a high rate of innate resistance, and VEGFA may contribute to ICI treatment resistance. In this study, we endeavored to assess the tumor microenvironment (TME) in VEGFA-overexpressed human tumors and mouse tumor models, and to explore whether anti-angiogenesis therapy can overcome the innate resistance to ICI in hyperangiogenesis mouse tumor models and the underlying mechanism. Effect of VEGFA on clinical prognosis and TME was analyzed using TCGA data. The VEGFA-overexpressed mouse breast and colon subcutaneous models were established. PD-1 mAb or apatinib alone and combination therapy were used. Immunohistochemistry and immunofluorescence were used to assess angiogenesis and hypoxia. Flow cytometry, RNA sequencing and MCP-counter were applied to detect tumor immunomicroenvironment. High level of VEGFA mRNA in human tumors is related to poor prognosis and hypoxic, angiogenic and immunosuppressive TME. Upregulation of VEGFA increased the degree of malignancy of tumor cells in vitro and in vivo. VEGFA-overexpressed models were characterized by hypoxic, hyperangiogenic and immunosuppressive TME and indicated innate resistance to ICI. In tumor-bearing mice without VEGFA overexpression, the combination therapy had no synergistic anti-tumor effect compared to monotherapy. However, apatinib alleviated hyperangiogenesis and hypoxia in TME and converted the immunosuppressive TME into an immunostimulatory one in VEGFA-overexpressed tumors. Thus, anti-angiogenesis therapy could improve the efficiency of ICI in VEGFA-overexpressed tumors. Revealing whether there is hypervascularization in tumor tissues may help to clarify the adoption of anti-angiogenesis and ICI combination therapy or ICI monotherapy in cancer treatment.

Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models

MicroRNA biogenesis, gene silencing mechanisms and role in breast, ovarian and prostate cancer.

MiR-221-3p targets ARF4 and inhibits the proliferation and migration of epithelial ovarian cancer cells.

// Xiaodan Fu 1, 2 , Yimin Li 1, 2 , Ayesha Alvero 3 , Juanni Li 1, 2 , Qihui Wu 1, 2 , Qing Xiao 1, 2 , Yulong Peng 1, 2 , Yongbin Hu 1, 2 , Xiang Li 1, 2 , Wenguang Yan 5 , Ke Guo 6 , Wenjuan Zhou 7 , Yong Wang 8 , Junwen Liu 9 , Yu Zhang 4 , Gil Mor 3 , Jifang Wen 1, 2 , Gang Yin 1, 2 1 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China 2 Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China 3 Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA 4 Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China 5 Department of Rehabilitation, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China 6 Department of Internal Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China 7 School of Nursing, Central South University, Changsha, Hunan Province, China 8 Department of Immunology, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China 9 Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China Correspondence to: Gang Yin, email: gang.yin@csu.edu.cn Jifang Wen, email: jifangwen@hotmail.com Keywords: ovarian cancer, miR-222-3p, GNAI2, pAKT, cell growth Received: June 19, 2016      Accepted: October 22, 2016      Published: November 02, 2016 ABSTRACT Ovarian carcinoma is the most lethal gynecologic tumor worldwide. Despite having developed molecular diagnostic tools and targeted therapies over the past few decades, patient survival is still quite poor. Numerous studies suggest that microRNAs are key regulators of many fundamental biological processes, including neoplasia and tumor progression. miR-222 is one of those miRNAs that has attracted much attention for its multiple roles in human diseases, especially cancer. The potential role of microRNAs in ovarian cancer has attracted much attention in recent years. Some of these microRNAs have been suggested as potential therapeutic targets for EOC patients. In this study, we sought to investigate the biologic functions of miR-222-3p in EOC carcinogenesis. Herein, we examined the expression of miR-222-3p in EOC patients, mouse models and cell lines, and found that higher expression of miR-222-3p was associated with better overall survival in EOC patients, and its level was negatively correlated with tumor growth in vivo . Furthermore, in-vitro experiments indicated that miR-222-3p inhibited EOC cell proliferation and migration, and decreased the phosphorylation of AKT. We identified GNAI2 as a target of miR-222-3p. We also found that GNAI2 promoted EOC cell proliferation, and is an activator of the PI3K/AKT pathway. We describe the characterization of a novel regulatory axis in ovarian cancer cells, miR-222-3p/GNAI2/AKT and its potential application as a therapeutic target for EOC patients.

/pdf/microrna-222-3p-gnai2-akt-axis-inhibits-epithelial-ovarian-zry6ai84jt.pdf

MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

5-hydroxytryptamine receptor 1A (5-HT1AR) is closely associated with cognitive functions. Selective serotonin reuptake inhibitors (SSRIs) can protect individuals from brain damage following ischemia/hypoxia. To investigate the function of SSRIs in vascular dementia (VD), we established a rat model of VD, and observed the effect of SSRIs on the expression of 5-HT1AR mRNA and neurotransmitters. Male SD rats (6 months) were randomly assigned into sham, model, and SSRI groups (N = 30). VD was achieved by permanent ligation of the bilateral common carotid artery. Escitalopram, a highly selective 5-HT reabsorption inhibitor, was ip injected into the rats for three consecutive weeks. The Morris water-maze was used to test learning and memory. H&E staining for neuronal injury was conducted on cortical and hippocampal tissues. HPLC was used to determine the levels of dopamine (DA), 5-HT, and norepinephrine (NE). RT-PCR was used to determine expression of 5-HT1AR mRNA. As compared to control rats, model animals demonstrated elongated escape latency, lower platform crossing times, and significant injuries to hippocampal CA1 neurons. This was accompanied by reductions in DA, 5-HT, and NE levels in hippocampal tissues, as well as reduced cortical 5-HT and decreased 5-HT1AR mRNA expression (P < 0.05). Escitalopram treatments reduced escape latency, elevated platform crossing times, improved CA1 neuronal damage, increased DA and 5-HT levels in hippocampal and cortical neurons, as well as elevated expression of 5-HT1AR mRNA (P < 0.05). Therefore, SSRIs may improve cognitive dysfunction of VD rats, possibly by stimulating expression of neurotransmitters and protecting neurons.

/pdf/effect-of-selective-serotonin-reuptake-inhibitors-on-1wn6x4jfn2.pdf

Effect of selective serotonin reuptake inhibitors on expression of 5-HT1AR and neurotransmitters in rats with vascular dementia.

Purpose: To investigate the expression and tyrosine 705 phosphorylation of STAT3 in focal cerebral ischemia-reperfusion rat model and its role in neuronal apoptosis.Methods: Ischemia-reperfusion model was established by thread-occluded method. Tetrazolium red (TTC), H/E and Nissl staining were used to evaluate whether ischemia-reperfusion model was successfully established. TUNEL staining and immunohistochemistry were employed to monitor apoptosis-positive nerve cells as well as STAT3-, p-Tyr705-STAT3-, Bcl-2- and Fas-positive cells in ischemic penumbra (IP) and ischemic core (IC).Results: The results of TTC, HE and Nissl staining indicated that the ischemia reperfusion model was successfully established. After 3 h, ischemia followed by different reperfusion times, the STAT3-, p- Tyr705-STAT3-, Fas- and Bcl-2 positive cells counts and the apoptosis-positive nerve cells count were significantly (p < 0.05 or 0.01) increased to 27.20, 29.20, 15.90, 18.50, and 202.00 in IP and 19.50, 21.20, 12.50, 12.40, and 97.80 in IC, compared with the sham-operated group. As reperfusion times increased, cell counts did not decrease significantly relative to control group. Correlation analysis indicate that there was significant (p < 0.01) positive correlations among STAT3-, p-Tyr705 STAT3-, Fas- and Bcl-2-positive cells counts on the one hand, and apoptosis positive nerve cells count in IP and IC, on the other hand.Conclusion: Regulating expression and tyrosine 705 phosphorylation of STAT3 may be a new and effective strategy for treating cerebral infarction.Keywords: Ischemia-reperfusion, Neuronal apoptosis, STAT3, Phosphorylation, Cerebral infarction

/pdf/a-study-on-expression-and-tyrosine-705-phosphorylation-of-3u5fte8dh9.pdf

A Study on Expression and Tyrosine 705 phosphorylation of STAT3 in Focal Cerebral Ischemia-Reperfusion Rat Model and its Role in Neuronal Apoptosis

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MiR-221-3p targets ARF4 and inhibits the proliferation and migration of epithelial ovarian cancer cells.

MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

Effect of selective serotonin reuptake inhibitors on expression of 5-HT1AR and neurotransmitters in rats with vascular dementia.

A Study on Expression and Tyrosine 705 phosphorylation of STAT3 in Focal Cerebral Ischemia-Reperfusion Rat Model and its Role in Neuronal Apoptosis