MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.

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The role and mechanisms of action of microRNAs in cancer drug resistance.

Traditional Chinese medicine (TCM) has been practiced for thousands of years and at the present time is widely accepted as an alternative treatment for cancer In this review, we sought to summarize the molecular and cellular mechanisms underlying the chemopreventive and therapeutic activity of TCM, especially that of the Chinese herbal medicine-derived phytochemicals curcumin, resveratrol, and berberine Numerous genes have been reported to be involved when using TCM treatments and so we have selectively highlighted the role of a number of oncogene and tumor suppressor genes in TCM therapy In addition, the impact of TCM treatment on DNA methylation, histone modification, and the regulation of noncoding RNAs is discussed Furthermore, we have highlighted studies of TCM therapy that modulate the tumor microenvironment and eliminate cancer stem cells The information compiled in this review will serve as a solid foundation to formulate hypotheses for future studies on TCM-based cancer therapy

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2108

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science.

How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB. Internalization of macrophages-secreted exosomes in EOC cells was detected by Confocal microscope. Subsequently, Dual-luciferase reporter assay verified PTEN was the target of miR-223. Gain- and loss-of-function experiments, rescue experiments, and SKOV3 xenograft models were performed to uncover the underlying mechanisms of miR-223 and PTEN-PI3K/AKT pathway, as well as the exosomal miR-223 in inducing multidrug resistance in vitro and in vivo. Here, we showed hypoxic EOC cells triggered macrophages recruitment and induced macrophages into a tumor-associated macrophage (TAM)-like phenotype; exosomes derived from hypoxic macrophages enhanced the malignant phenotype of EOC cells, miR-223 was enriched in exosomes released from macrophages under hypoxia, which could be transferred to the co-cultivated EOC cells, accompanied by enhanced drug resistant of EOC cells. Besides, results from a functional assay revealed that exosomal miR-223 derived from macrophages promoted the drug resistance of EOC cells via the PTEN-PI3K/AKT pathway both in vivo and in vitro. Furthermore, patients with high HIF-1a expression had statistically higher CD163+ cell infiltration and intertumoral levels of miR-223. Finally, circulating exosomal miR-223 levels were closely related to the recurrence of EOC. These data indicate a unique role of exosomal miR-223 in the cross-talk between macrophages and EOC cells in chemotherapy resistance, through a novel exosomal miR-223/PTEN-PI3K/AKT signaling pathway.

/pdf/macrophages-derived-exosomes-deliver-mir-223-to-epithelial-41syr987br.pdf

Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype.

Long non-coding RNAs (LncRNAs) represent a novel class of noncoding RNAs that are longer than 200 nucleotides without protein-coding potential and function as novel master regulators in various human diseases, including cancer. Accumulating evidence shows that lncRNAs are dysregulated and implicated in various aspects of cellular homeostasis, such as proliferation, apoptosis, mobility, invasion, metastasis, chromatin remodeling, gene transcription, and post-transcriptional processing. However, the mechanisms by which lncRNAs regulate various biological functions in human diseases have yet to be determined. HOX antisense intergenic RNA (HOTAIR) is a recently discovered lncRNA and plays a critical role in various areas of cancer, such as proliferation, survival, migration, drug resistance, and genomic stability. In this review, we briefly introduce the concept, identification, and biological functions of HOTAIR. We then describe the involvement of HOTAIR that has been associated with tumorigenesis, growth, invasion, cancer stem cell differentiation, metastasis, and drug resistance in cancer. We also discuss emerging insights into the role of HOTAIR as potential biomarkers and therapeutic targets for novel treatment paradigms in cancer.

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HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer.

Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the treatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.

Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs

Background: Berberine, a well-known component of the Chinese herbal medicine Huanglian, has wide range of biochemical and pharmacological effects, including antineoplastic effect, but the exact mechanisms remain unclear. The aim of the present study was to evaluate the potential chemo-sensitization effect of berberine in ovarian cancer cell line A2780. Methods: The expression of miR-93 was measure by RT-PCR. The target of miR-93 was confirmed by luciferase activity assay. Hoechst 33258 staining, Annexin V and PI double staining were used for apoptosis analysis. Results: In this study, we found A2780/DDP cells that were incubated with berberine combined with cisplatin had a significantly lower survival than the control group. Berberine enhanced cisplatin induced apoptosis and induced G0/G1 cell cycle arrest in A2780 cells. Next, we observed that the miR-93 levels in cisplatin resistant cell lines were higher than that in cisplatin sensitive cell lines. Furthermore, our study found berberine could inhibit miR-93 expression and function in ovarian cancer, as shown by an increase of its target PTEN, an important tumor suppressor in ovarian cancer. A2780 cells that were treated with PTEN siRNA had increased survival compared to NC group and this could be partly alleviated by the AKT inhibitor Triciribine. More importantly, A2780 cells that were treated with PTEN siRNA had a survival pattern that is similar to cells with miR-93 overexpression. Conclusion: The results suggested that berberine modulated the sensitivity of cisplatin through miR-93/PTEN/AKT signaling pathway in the ovarian cancer cells.

/pdf/berberine-sensitizes-human-ovarian-cancer-cells-to-cisplatin-4me1ttgcjc.pdf

Berberine Sensitizes Human Ovarian Cancer Cells to Cisplatin Through miR-93/PTEN/Akt Signaling Pathway.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. Platinum-based chemotherapy is the first-line treatment for the advanced ovarian cancer, but resistance to cisplatin remains a major obstacle to successful treatment. MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in disease processes, including the development of drug resistance. In this study, we found miR-449a were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. The overexpression of miR-449a increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis. The luciferase assay confirmed that miR-449a functioned through suppressing NOTCH1 directly. Concordantly, BALB/c nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-449a mimics exhibited enhanced cisplatin sensitivity in vivo. Taken together, these results suggest that the ectopic expression of miR-449a may be a promising therapeutic strategy for the management of cisplatin resistance in ovarian cancer.

MicroRNA-449a reduces cell survival and enhances cisplatin-induced cytotoxicity via downregulation of NOTCH1 in ovarian cancer cells

Background/Aims: The HOX transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA (lncRNA), plays an important role in the pathogenesis and progression

/pdf/association-of-functional-genetic-variants-of-hotair-with-1dc8bysbax.pdf

Association of Functional Genetic Variants of HOTAIR with Hepatocellular Carcinoma (HCC) Susceptibility in a Chinese Population

Background and Aims: Single nucleotide polymorphisms in miRNA binding sites, which are located in mRNA 3' untranslated regions (3'-UTRs), were recently found to influence microRNA-target interactions. Specifically, such polymorphisms can modulatebinding affinity or create or destroy miRNA-binding sites; such variants have also been found to be associated with cancer risk. In this study, we explored the effect of a functional variant at the miR-214 binding site in the methylenetetrahydrofolate reductase gene (rs114673809) on gastric cancer (GC) risk in a hospital-based case-control study in a Chinese Han population. Methods and Results: We genotyped the rs114673809 polymorphism in 345 gastric cancer patients and 376 cancer-free controls using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The functions of rs114673809 were investigated using a luciferase activity assay and validated by immunoblotting. We found that participants carrying the rs114673809 AA genotype or A allele had a significantly increased risk of gastric cancer (OR = 1.667, 95% CI = 1.044-2.660, P = 0.034; OR = 1.261, 95% CI = 1.017-1.563, P = 0.037, respectively) compared to those carrying the GG genotype and G allele. In addition, rs114673809 modified the binding of hsa-miR-214 to MTHFR as well as MTHFR protein levels in gastric cancer patients. Conclusion: Our data suggested that rs114673809, which is located at the miR-214 binding site in the 3'-UTR of MTHFR, may play an important role in the development of gastric cancer in a Chinese Han population.

/pdf/a-functional-variant-at-the-mir-214-binding-site-in-the-bzuq4pael7.pdf

A Functional Variant at the miR-214 Binding Site in the Methylenetetrahydrofolatereductase Gene Alters Susceptibility to Gastric Cancer in a Chinese Han Population

An increasing body of evidence has indicated that polymorphisms in the miRNA binding site of target gene can alter the ability of miRNAs to bind their target genes and modulate the risk of cancer. We aimed to investigate the association between a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3′-UTR and the risk of colorectal cancer (CRC) in a Chinese Han population. The polymorphism rs141178472 was analyzed in a case-control study, including 386 CRC patients and 394 age- and sex-matched controls; the relationship between the polymorphism and the risk of colorectal cancer was examined. Individuals carrying the rs141178472 CC genotype or C allele had an increased risk of developing CRC (CC versus TT, OR (95% CI): 1.716 (1.084–2.716), P = 0.022; C versus T, OR (95% CI): 1.258 (1.021–1.551), P = 0.033). Furthermore, the expression of PIK3CA was detected in the peripheral blood mononucleated cell of CRC patients, suggesting that mRNA levels of PIK3CA might be associated with SNP rs141178472. These findings provide evidence that a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3′-UTR may play a role in the etiology of CRC.

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Hao Li

Papers

Berberine Sensitizes Human Ovarian Cancer Cells to Cisplatin Through miR-93/PTEN/Akt Signaling Pathway.

MicroRNA-449a reduces cell survival and enhances cisplatin-induced cytotoxicity via downregulation of NOTCH1 in ovarian cancer cells

Association of Functional Genetic Variants of HOTAIR with Hepatocellular Carcinoma (HCC) Susceptibility in a Chinese Population

A Functional Variant at the miR-214 Binding Site in the Methylenetetrahydrofolatereductase Gene Alters Susceptibility to Gastric Cancer in a Chinese Han Population

A Functional Variant at miR-520a Binding Site in PIK3CA Alters Susceptibility to Colorectal Cancer in a Chinese Han Population