MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.

/pdf/dysregulation-of-micrornas-in-breast-cancer-and-their-15zdi40hyn.pdf

Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management.

In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes. SIRT3 is well known for its ability to eliminate reactive oxygen species and to prevent the development of cancerous cells or apoptosis. This review article provides a comprehensive review on numerous (noteworthy) molecular functions of SIRT3 and its effect on cancer cells and various diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12538

Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease.

Cervical cancer: Biomarkers for diagnosis and treatment.

There is accumulating evidence indicating that aldehyde dehydrogenase (ALDH) activity selects for cancer cells with increased aggressiveness, capacity for sustained proliferation, and plasticity in primary tumors. However, emerging data also suggests an important mechanistic role for the ALDH family of isoenzymes in the metastatic activity of tumor cells. Recent studies indicate that ALDH correlates with either increased or decreased metastatic capacity in a cellular context-dependent manner. Importantly, it appears that different ALDH isoforms support increased metastatic capacity in different tumor types. This review assesses the potential of ALDH as biological marker and mechanistic mediator of metastasis in solid tumors. In many malignancies, most notably in breast cancer, ALDH activity and expression appears to be a promising marker and potential therapeutic target for treating metastasis in the clinical setting.

/pdf/aldehyde-dehydrogenase-as-a-marker-and-functional-mediator-1h04ltlpyy.pdf

Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors

Owing to late diagnosis in advanced disease stages, prognosis of patients with epithelial ovarian cancer (EOC) is poor. The quantification of deregulated levels of microRNAs could facilitate earlier diagnosis and improve prognosis of EOC. Seven microRNAs (miR-7, miR-16, miR-25, miR-93, miR-182, miR-376a and miR-429) were quantified in the serum of 180 EOC patients and 66 healthy women by TaqMan PCR microRNA assays. Median follow-up time was 21 months. The effects of miR-7 and miR-429 on apoptosis, cell proliferation, migration and invasion were investigated in two (EOC) cell lines. Serum levels of miR-25 (P=0.0001) and miR-93 (P=0.0001) were downregulated, whereas those of miR-7 (P=0.001) and miR-429 (P=0.0001) were upregulated in EOC patients compared with healthy women. The four microRNAs discriminated EOC patients from healthy women with a sensitivity of 93% and a specificity of 92%. The levels of miR-429 positively correlated with CA125 values (P=0.0001) and differed between FIGO I–II and III–IV stages (P=0.001). MiR-429 was an independent predictor of overall survival (P=0.011). Overexpressed miR-429 in SKOV3 cells led to suppression of cell migration (P=0.037) and invasion (P=0.011). Increased levels of miR-7 were associated with lymph node metastases (P=0.0001) and FIGO stages III–IV (P=0.0001). Overexpressed miR-7 in SKOV3 cells resulted in increased cell migration (P=0.001) and invasion (P=0.011). Additionally, the increased levels of miR-376a correlated with FIGO stages III–IV (P=0.02). Our data indicate the diagnostic potential of miR-7, miR-25, miR-93 and miR-429 in EOC and the prognostic potential of miR-429. This microRNA panel may be promising molecules to be targeted in the treatment of EOC.

/pdf/diagnostic-and-prognostic-potential-of-serum-mir-7-mir-16-3grnb7p6jk.pdf

Diagnostic and prognostic potential of serum miR-7, miR-16, miR-25, miR-93, miR-182, miR-376a and miR-429 in ovarian cancer patients.

Everolimus, an oral inhibitor of mammalian target of mTOR, has been recently shown to have antitumor effect in a phase III, double-blind, randomized trial (RADIANT-3) of 410 patients with advanced pancreatic neuroendocrine tumors (PNETs). The purpose of this study was to investigate the specific efficacy and safety of everolimus in the Chinese patient with PNETs. In this randomized phase II study, the analysis on Chinese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 44) and matching placebo (n = 35). The primary endpoint was progression-free survival (PFS). Adverse events were also examined. The median PFS was 15.47 months with everolimus [95 % confidence interval (CI) 10.52–26.37], as compared to 4.29 months with placebo (95 % CI 2.22–10.75), representing a 72 % reduction in the risk of progression or death (hazard ratio 0.27; 95 % CI 0.13–0.59; P < 0.001). Drug-associated adverse events (AEs) were mostly grade 1 or 2, observed in all 44 (100 %) patients receiving everolimus and in 29 (83 %) patients receiving placebo. The most common AEs (grade 1–4) associated with everolimus were rash (n = 38; 86 %), stomatitis (n = 30; 68 %), infections (n = 33; 75 %), epistaxis (n = 32; 73 %), pneumonitis (n = 27; 61 %) and anemia (n = 22; 50 %). Everolimus when compared with placebo is effectively in improving PFS in Chinese patients with PNETs.

/pdf/retraction-note-to-a-randomized-phase-ii-study-of-everolimus-3gz3h16dc8.pdf

Retraction Note to: A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) the etiology of which has not yet been fully clarified. Cytokine interleukin-10 (IL-10) plays a central role in downregulating inflammatory cascade in UC and is likely a candidate for therapeutic intervention. However, its intravenous administration is costly and inconvenient. Therefore, we established a novel IL-10 delivery system by transforming a hIL-10-containing plasmid into B. longum (BL-hIL-10) and investigated its effects on 5% dextran sulfate sodium (DSS)-induced ulcerative colitis in mice and the possible underlying mechanism. Our results show that (1) hIL-10 was expressed and secreted into the culture supernatant of BL-hIL-10 after L-arabinose induction in vitro as examined by Western blot, enzyme-linked immunosorbent assay (ELISA) and RT-PCR; (2) addition of BL-hIL-10 culture supernatant had no cytotoxic effect and morphological alteration, but significantly inhibited the enhancement of proinflammatory cytokines by lipopolysaccharide (LPS) in THP-1 cells; (3) oral administration of BL-hIL-10 alleviated colitis syndrome of the model mice, attenuated colitis-activated NF-κB pathway measured by DNA-binding assay and colitis-elevated expression of proinflammatory cytokines examined with CCK cytotoxic kits, and upregulated CD4+CD25+Foxp3+ Treg in blood and mesenteric lymph nodes measured by flow cytometry. In conclusion, BL-hIL-10 as a novel oral hIL-10 delivery system has been successfully established and oral administration of BL-hIL-10 alleviated inflammatory damage of colonic tissue in the model mice by blocking the colitis-activated NF-κB pathway and upregulating CD4+CD25+Foxp3+ Treg in blood and mesenteric lymph nodes in mice.

Treatment of Mice with Dextran Sulfate Sodium-Induced Colitis with Human Interleukin 10 Secreted by Transformed Bifidobacterium longum

Everolimus, an oral inhibitor of mammalian target of mTOR, has been recently shown to have antitumor effect in a phase III, double-blind, randomized trial (RADIANT-3) of 410 patients with advanced pancreatic neuroendocrine tumors (PNETs). The purpose of this study was to investigate the specific efficacy and safety of everolimus in the Chinese patient with PNETs. In this randomized phase II study, the analysis on Chinese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 44) and matching placebo (n = 35). The primary endpoint was progression-free survival (PFS). Adverse events were also examined. The median PFS was 15.47 months with everolimus [95% confidence interval (CI) 10.52-26.37], as compared to 4.29 months with placebo (95% CI 2.22-10.75), representing a 72% reduction in the risk of progression or death (hazard ratio 0.27; 95% CI 0.13-0.59; P < 0.001). Drug-associated adverse events (AEs) were mostly grade 1 or 2, observed in all 44 (100%) patients receiving everolimus and in 29 (83%) patients receiving placebo. The most common AEs (grade 1-4) associated with everolimus were rash (n = 38; 86%), stomatitis (n = 30; 68%), infections (n = 33; 75%), epistaxis (n = 32; 73%), pneumonitis (n = 27; 61%) and anemia (n = 22; 50%). Everolimus when compared with placebo is effectively in improving PFS in Chinese patients with PNETs.

A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients.

Induction of apoptotic DNA fragmentation mediated by mitochondrial pathway with caspase-3-dependent BID cleavage in human gastric cancer cells by a new nitroxyl spin-labeled derivative of podophyllotoxin.

3-Phosphoinositide-dependent protein kinase 1 (PDK1) is centrally involved in cancer progression, including proliferation, apoptosis and invasion. However, its expression pattern and possible cellular functions in human colorectal cancer remain unclear. In the present study, we show that PDK1 expression is up-regulated at both mRNA and protein levels in colorectal cancer clinical specimens and cell lines. Transient knockdown of PDK1 suppresses cellular growth, induces cellular apoptosis and causes abnormal cell cycle distribution. Meanwhile, decreased PDK1 level is closely associated with reduced Akt/cyclin D1 activity. Activating AKT activity and reintroducing cyclin D1 expression significantly compromised the oncogenic activity induced by PDK1. Together, our findings elucidate a key role for PDK1 in colorectal cellular functions trigged by the Akt/cyclin D1 pathway, thus providing a novel insight of PDK1 in colorectal carcinogenesis.

Li-Sheng Wang

Papers

Retraction Note to: A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients

Treatment of Mice with Dextran Sulfate Sodium-Induced Colitis with Human Interleukin 10 Secreted by Transformed Bifidobacterium longum

A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients.

Induction of apoptotic DNA fragmentation mediated by mitochondrial pathway with caspase-3-dependent BID cleavage in human gastric cancer cells by a new nitroxyl spin-labeled derivative of podophyllotoxin.

Expression of 3-phosphoinositide-dependent protein kinase 1 in colorectal cancer as a potential therapeutic target