Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation. 

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The long and short non-coding RNAs modulating EZH2 signaling in cancer

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.

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Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

Breast cancer is the most commonly occurring cancer in women worldwide, and the rate of diagnosis continues to increase. Early detection and targeted treatment towards histological type is crucial to improving outcomes, but current screening methods leave some patients at risk of late diagnosis. The risk of late diagnosis and progressed disease is of particular concern for young women as current screening methods are not recommended early in life. Aptamers are oligonucleotides that can bind with high specificity to target molecules such as proteins, peptides, and other small molecules. They are relatively cheap to produce and are invariable from batch to batch, making them ideal for use in large-scale clinical or screening programs. The use of aptamers for breast cancer screening, diagnosis, and therapeutics is promising, but comparison of these aptamers and their corresponding biomarkers for use in breast cancer is significantly lacking. Here, we compare the currently available aptamers for breast cancer biomarkers and their respective biomarkers, as well as highlight the electrochemical sensors that are in development.

Breast Cancer Aptamers: Current Sensing Targets, Available Aptamers, and Their Evaluation for Clinical Use in Diagnostics

Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. Periostin is an extracellular matrix protein highly expressed in the lung tissues of IPF. This study aimed to investigate the possibility that periostin secreted by fibroblasts derived from IPF lung might affect proliferation of NSCLC cells. Periostin was more highly expressed and secreted by fibroblasts from diseased human lung with IPF (DIPF) than by normal human lung fibroblasts (NHLF). Cocultivation of NSCLC cells with conditioned media (CM) from DIPF increased proliferation of NSCLC cells through pErk signaling, with this proliferation attenuated by periostin-neutralizing antibodies. Knockdown of integrin β3, a subunit of the periostin receptor, in NSCLC cells suppressed proliferation of NSCLC cells promoted by recombinant human periostin and CM of DIPF. On in vivo examination, DIPF promoted tumor progression more than NHLF, and knockdown of integrin β3 in NSCLC cells suppressed tumor progression promoted by DIPF. Fibroblasts derived from surgical specimens from IPF patients also increased secretion of periostin compared to those from non-IPF patients. Periostin secreted from IPF-activated fibroblasts plays critical roles in the proliferation of NSCLC cells. The present study provides a solid basis for considering periostin-targeted therapy for NSCLC patients with IPF.

/pdf/periostin-secreted-by-activated-fibroblasts-in-idiopathic-1f7xozx53z.pdf

Periostin secreted by activated fibroblasts in idiopathic pulmonary fibrosis promotes tumorigenesis of non-small cell lung cancer.

Breast cancer (BCa) is the leading cause of cancer deaths among women. Reliable biomarkers for early diagnosis and metastasis prediction are essential to improve the prognosis of BCa. This study aimed to evaluate serum periostin (POSTN) as a novel biomarker complementing CA153 (carbohydrate antigen 153) and CEA (carcinoembryonic antigen) for BCa diagnosis and metastasis prediction.To assess the potential of soluble POSTN as a circulating biomarker, 242 participants, including 173 patients with different stages of BCa and 69 healthy individuals, were enrolled in this study. Soluble POSTN, together with CA153 and CEA, were determined in serum by enzyme linked immunosorbent assay (ELISA) or electrochemiluminescence immunoassays.Serum POSTN levels in locoregional BCa patients were significantly higher than that in healthy controls. Receiver operating curve (ROC) analysis revealed that, to distinguish health controls from locoregional BCa, POSTN was observed with the highest AUC (area under curve) (AUCPOSTN = 0.72 [0.65 - 0.79], AUCCA153 = 0.57 [0.49 - 0.64], AUCCEA = 0.62 [0.55 - 0.69]), and both CA153 and CEA were observed with significantly improved AUCs by combination with POSTN (AUCPOSTN + CA153 = 0.74 [0.67 - 0.80], P < 0.001; AUCPOSTN + CEA = 0.77 [0.70 - 0.82], P < 0.001). Moreover, the performances of the POSTN were comparable with that of CA153 in predicting distant metastasis of BCa (AUCPOSTN = 0.78 [0.71 - 0.84], AUCCA153 = 0.82 [0.76 - 0.88]). Kaplan-Meier analysis indicated that elevated serum POSTN was associated with poor overall survival and progression-free survival.This study suggested that soluble POSTN is a promising potential biomarker for diagnosis and metastasis prediction of BCa. 

/pdf/soluble-postn-is-a-novel-biomarker-complementing-ca153-and-3bf4yj6l.pdf

Soluble POSTN is a novel biomarker complementing CA153 and CEA for breast cancer diagnosis and metastasis prediction

Chemoresistance is one of the main problems in treatment of cancer. Periostin (PN) is a stromal protein which is mostly secreted from cancer associated fibroblasts in the tumor microenvironment and can promote cancer progression including cell survival, metastasis, and chemoresistance. The main objective of this study was to develop an anti-PN peptide from the bacteriophage library to overcome PN effects in breast cancer (BCA) cells. A twelve amino acids bacteriophage display library was used for biopanning against the PN active site. A selected clone was sequenced and analyzed for peptide primary structure. A peptide was synthesized and tested for the binding affinity to PN. PN effects including a proliferation, migration and a drug sensitivity test were performed using PN overexpression BCA cells or PN treatment and inhibited by an anti-PN peptide. An intracellular signaling mechanism of inhibition was studied by western blot analysis. Lastly, PN expressions in BCA patients were analyzed along with clinical data. The results showed that a candidate anti-PN peptide was synthesized and showed affinity binding to PN. PN could increase proliferation and migration of BCA cells and these effects could be inhibited by an anti-PN peptide. There was significant resistance to doxorubicin in PN-overexpressed BCA cells and this effect could be reversed by an anti-PN peptide in associations with phosphorylation of AKT and expression of survivin. In BCA patients, serum PN showed a correlation with tissue PN expression but there was no significant correlation with clinical data. This finding supports that anti-PN peptide is expected to be used in the development of peptide therapy to reduce PN-induced chemoresistance in BCA.

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Khine Kyaw Oo

Papers

Development of an engineered peptide antagonist against periostin to overcome doxorubicin resistance in breast cancer.