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

Tumor metastasis is not only a sign of disease severity but also a major factor causing treatment failure and cancer-related death. Therefore, studies on the molecular mechanisms of tumor metastasis are critical for the development of treatments and for the improvement of survival. The epithelial-mesenchymal transition (EMT) is an orderly, polygenic biological process that plays an important role in tumor cell invasion, metastasis and chemoresistance. The complex, multi-step process of EMT involves multiple regulatory mechanisms. Specifically, the PI3K/Akt signaling pathway can affect the EMT in a variety of ways to influence tumor aggressiveness. A better understanding of the regulatory mechanisms related to the EMT can provide a theoretical basis for the early prediction of tumor progression as well as targeted therapy.

https://www.tandfonline.com/doi/pdf/10.1080/19336918.2015.1016686

A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition.

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Accumulating evidence has revealed that aberrant Circular RNAs (circRNAs) expression plays important roles in carcinogenesis and tumor progression. However, their role in non-small cell lung cancer (NSCLC) remains unclear. In this study, we first used circRNA microarrays to screen for tumour-specific circRNA candidates in between NSCLC (n = 3) and adjacent lung (n = 3) tissue. Among the circRNA expression profile, two circRNAs (hsa_circ_0014130 and hsa_circ_0016760) were selected for validation in ten pairs of NSCLC and adjacent non-cancerous tissues by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Only hsa_circ_0014130 exhibited significantly overexpressed in NSCLC tissues (P < 0.001), which were further confirmed in another 36 matched tissue samples using qRT-PCR. Hsa_circ_0014130 expression significantly correlated with TNM stage (P = 0.001) and lymphatic metastasis (P = 0.004). The area under the receiver operating characteristic curve was 0.878 (95% confidence interval = 0.804–0.951; P < 0.001), which showed good diagnostic potential. Bioinformatics platforms predicted that hsa_circ_0014130 might interact with five miRNAs and their corresponding mRNAs. Gene oncology analysis and pathway analysis revealed that hsa_circ_0014130 could participate in NSCLC development. In summary, our findings indicated that hsa_circ_0014130 could be used as a potential NSCLC biomarker and might be closely related to the carcinogenesis of NSCLC.

/pdf/microarray-profile-of-circular-rnas-identifies-hsa-circ-1wes7mtzcv.pdf

Microarray profile of circular RNAs identifies hsa_circ_0014130 as a new circular RNA biomarker in non-small cell lung cancer.

Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among breast cancer patients. This study was aimed to investigate the possible mechanism by which microRNA-130b-3p (miR-130b) mediates the chemoresistance and proliferation of breast cancer. MiR-130b was found to be up-regulated in tumor tissues versus adjacent tissues of breast cancer, as well as in adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) versus its parental line (MCF-7) and the non-malignant breast epithelial cell line (MCF-10A), demonstrating its crucial relevance for breast cancer biology. We identified that PTEN was a direct target of miR-130b and inversely correlated with miR-130b expression in breast cancer. Moreover, over-expression of miR-130b promoted drug resistance, proliferation and decreased apoptosis of MCF-7 cells, while suppression of miR-130b enhanced drug cytotoxicity and apoptosis, as well as reduced proliferation of MCF-7/ADR cells in vitro and in vivo. Particularly, miR-130b mediated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway as well as the chemoresistance and proliferation of breast cancer cell lines, which was partially blocked following knockdown of PTEN. Altogether, miR-130b targets PTEN to induce MDR, proliferation, and apoptosis via PI3K/Akt signaling pathway. This provides a novel promising candidate for breast cancer therapy.

/pdf/microrna-130b-targets-pten-to-mediate-drug-resistance-and-21yezne83e.pdf

MicroRNA-130b targets PTEN to mediate drug resistance and proliferation of breast cancer cells via the PI3K/Akt signaling pathway.

The fucosyltransferase (FUT) family is the key enzymes in cell-surface antigen synthesis during various biological processes such as tumor multidrug resistance (MDR) The aim of this work was to analyze the alteration of FUTs involved in MDR in human hepatocellular carcinoma (HCC) cell lines Using mass spectrometry (MS) analysis, the composition profiling of fucosylated N-glycans differed between drug-resistant BEL7402/5-FU (BEL/FU) cells and the sensitive line BEL7402 Further analysis of the expressional profiles of the FUT family in three pairs of parental and chemoresistant human HCC cell lines showed that FUT4, FUT6 and FUT8 were predominant expressed in MDR cell lines The altered levels of FUT4, FUT6 and FUT8 were responsible for changed drug-resistant phenotypes of BEL7402 and BEL/FU cells both in vitro and in vivo In addition, regulating FUT4, FUT6 or FUT8 expression markedly modulated the activity of the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway and MDR-related protein 1 (MRP1) expression Inhibition of the PI3K/Akt pathway by its specific inhibitor wortmannin, or by Akt small interfering RNA (siRNA), resulted in decreased MDR of BEL/FU cells, partly through the downregulation of MRP1 Taken together, our results suggest that FUT4-, FUT6- or FUT8-mediated MDR in human HCC is associated with the activation of the PI3K/Akt pathway and the expression of MRP1, but not of P-gp, indicating a possible novel mechanism by which the FUT family regulates MDR in human HCC

/pdf/fut-family-mediates-the-multidrug-resistance-of-human-37u2gvxy2y.pdf

FUT family mediates the multidrug resistance of human hepatocellular carcinoma via the PI3K/Akt signaling pathway

// Lei Cheng 1, 2, * , Shuhang Gao 3, * , Xiaobo Song 4 , Weijie Dong 5 , Huimin Zhou 6 , Lifen Zhao 1 , Li Jia 1 1 College of Laboratory Medicine, Dalian Medical University, Dalian 116044, Liaoning Province, China 2 Department of Laparoscopic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China 3 Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China 4 Department of Medical Biology, Faculty of Health Sciences, University of Tromso, Tromso, Norway 5 Department of Biochemistry, Dalian Medical University, Dalian 116044, Liaoning Province, China 6 Department of Microbiology, Dalian Medical University, Dalian 116044, Liaoning Province, China * These authors contributed equally to this work Correspondence to: Li Jia, email: jiali0386@sina.com Keywords: fucosyltransferase (FUT) gene, human hepatocellular carcinoma cell lines, tumor progression, microRNAs Received: February 05, 2016      Accepted: August 09, 2016      Published: August 13, 2016 ABSTRACT Glycosylation has significant effects on cancer progression. Fucosylation is one of the most important glycosylation events involved in hepatocellular carcinoma (HCC). Here, we compared N-glycan profiles of liver tumor tissues and adjacent tissues of 27 HCC patients to reveal the association between fucosylation and HCC progression, as well as verified the potential role of miRNA in regulating fucosylation. Mass spectrometry (MS) analysis showed pronounced differences of the N-glycosylation patterns and fucosylated N-glycans between the adjacent and tumor tissues. Different fucosyltransferase (FUT) genes were also identified in adjacent and tumor tissues, and two HCC cell lines with different metastatic potential. High-level expression of FUT8 was detected in tumor tissues and highly metastatic HCC cells. Altered levels of FUT8 in HCC cell lines significantly linked to the malignant behaviors of proliferation and invasion in vitro . Furthermore, using microRNA array, we identified FUT8 as one of the miR-26a, miR-34a and miR-146a-targeted genes. An inverse correlation was revealed between the expression levels of FUT8 and these miRNAs. Luciferase reporter assay demonstrated these miRNAs specifically interacted with the 3′UTR of FUT8 and subsequently down-regulated FUT8 expression-level. The forced expression of these miRNAs was able to induce a decrease in FUT8 levels and thereby to suppress HCC cells progression. Altogether, our results indicate that fucosylated N -glycan and FUT8 levels can be used as markers for evaluating HCC progression, as well as miRNAs may be involved in inhibition of fucosylation machinery through targeting FUT8.

/pdf/comprehensive-n-glycan-profiles-of-hepatocellular-carcinoma-2a9l4ztno5.pdf

Comprehensive N-glycan profiles of hepatocellular carcinoma reveal association of fucosylation with tumor progression and regulation of FUT8 by microRNAs

β-galactoside α2, 6-sialyltransferse gene (ST6GAL) family has two members, which encode corresponding enzymes ST6Gal I and ST6Gal II. The present atudy was to investigate whether and how ST6GAL family involved in multidrug resistance (MDR) in human leukemia cell lines and bone marrow mononuclear cells (BMMC) of leukemia patients. Real-time PCR showed a high expression level of ST6GAL1 gene in both MDR cells and BMMCs (*P<0.05). Alternation of ST6GAL1 levels had a significant impact on drug-resistant phenotype changing of K562 and K562/ADR cells both in vitro and in vivo. However, no significant changes were observed of ST6GAL2 gene. Further data revealed that manipulation of ST6GAL1 modulated the activity of phosphoinositide 3 kinase (PI3K)/Akt signaling and consequently regulated the expression of P-glycoprotein (P-gp, *P<0.05) and multidrug resistance related protein 1 (MRP1, *P<0.05), which are both known to be associated with MDR. Therefore we postulate that ST6GAL1 is responsible for the development of MDR in human leukemia cells probably through medicating the activity of PI3K/Akt signaling and the expression of P-gp and MRP1.

/pdf/reversal-effect-of-st6gal-1-on-multidrug-resistance-in-human-2stjjryahe.pdf

Reversal effect of ST6GAL 1 on multidrug resistance in human leukemia by regulating the PI3K/Akt pathway and the expression of P-gp and MRP1

Increased fucosylation has a pivotal role in multidrug resistance of breast cancer cells through miR-224-3p targeting FUT4.

Breast cancer is a leading cause of cancer-related mortality among women. Altered fucosylation was found to be closely associated with tumorigenesis and metastasis of breast cancer. MicroRNAs (miRNAs) are important regulators of cell proliferation and metastasis, and aberrant miRNA expression has been observed in breast cancer. The present study aimed to evaluate the level of fucosyltransferase IV (FUT4) and miR-493-5p in breast cancer and investigate their relationship. In the present study, we demonstrated the differential expressional profiles of FUT4 and miR‑493-5p in 29 clinical breast cancer tissues, matched adjacent tissue samples and two breast carcinoma cell lines (MCF-7 and MDA-MB-231). Briefly, altered expression levels of FUT4 modified the invasive activities and tumorigenicity of the MCF-7 and MDA-MB-231 cells. Further study demonstrated that miR-493-5p plays a role as a suppressor in breast cancer cell invasion and tumorigenicity. Moreover, the expression levels of miR-493-5p were inversely proportional to those of FUT4 both at the mRNA and protein levels. Luciferase reporter assays confirmed that miR‑493-5p bound to the 3'-untranslated (3'-UTR) region of FUT4, and inhibited the expression of FUT4 in breast cancer cells. Taken together, our data suggest that FUT4 may have a potential role in the treatment of breast cancer, as well as miR-493-5p is a novel regulator of invasiveness and tumorigenicity of breast cancer cells through targeting FUT4. The miR-493-5p/FUT4 pathway has therapeutic potential in breast cancer.

/pdf/mir-493-5p-attenuates-the-invasiveness-and-tumorigenicity-in-gglabuhx7i.pdf

Lei Cheng

Papers

FUT family mediates the multidrug resistance of human hepatocellular carcinoma via the PI3K/Akt signaling pathway

Comprehensive N-glycan profiles of hepatocellular carcinoma reveal association of fucosylation with tumor progression and regulation of FUT8 by microRNAs

Reversal effect of ST6GAL 1 on multidrug resistance in human leukemia by regulating the PI3K/Akt pathway and the expression of P-gp and MRP1

Increased fucosylation has a pivotal role in multidrug resistance of breast cancer cells through miR-224-3p targeting FUT4.

miR-493-5p attenuates the invasiveness and tumorigenicity in human breast cancer by targeting FUT4.