Oral submucous fibrosis(OSF)is a chronic and inflammatory mucosal disease caused by betel quid chewing,which belongs to oral potentially malignant disorders.Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development.The epithelium,which is the first line of defense against the external environment,can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment.However,the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear.In this study,we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes.MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts,where it promoted cell secretion,contraction,migration and fibrogenic marker(α-SMA and collagen type I)expression.The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1(TGFBR1)through the E3 ubiquitination ligase WWP1,thus facilitating downstream TGF-β pathway signaling.Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes.Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts.In conclusion,we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway,which provided a new perspective and strategy for the diagnosis and treatment of OSF.

Oral submucous fibrosis(OSF)is a chronic and inflammatory mucosal disease caused by betel quid chewing,which belongs to oral potentially malignant disorders.Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development.The epithelium,which is the first line of defense against the external environment,can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment.However,the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear.In this study,we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes.MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts,where it promoted cell secretion,contraction,migration and fibrogenic marker(α-SMA and collagen type I)expression.The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1(TGFBR1)through the E3 ubiquitination ligase WWP1,thus facilitating downstream TGF-β pathway signaling.Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes.Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts.In conclusion,we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway,which provided a new perspective and strategy for the diagnosis and treatment of OSF.

Cancer is a major threat to human health and causes death worldwide. Research on the role of radiotherapy (RT) in the treatment of cancer is progressing; however, RT not only causes fatal DNA damage to tumor cells, but also affects the interactions between tumor cells and different components of the tumor microenvironment (TME), including immune cells, fibroblasts, macrophages, extracellular matrix, and some soluble products. Some cancer cells can survive radiation and have shown strong resistance to radiation through interaction with the TME. Currently, the complex relationships between the tumor cells and cellular components that play major roles in various TMEs are poorly understood. This review explores the relationship between RT and cell-cell communication in the TME from the perspective of immunity and hypoxia and aims to identify new RT biomarkers and treatment methods in lung cancer to improve the current status of unstable RT effect and provide a theoretical basis for further lung cancer RT sensitization research in the future.
Humans ; Neoplasms/pathology* ; Lung Neoplasms/complications* ; Fibroblasts/pathology* ; Biomarkers ; Macrophages/pathology* ; Hypoxia ; Tumor Microenvironment

Objective To discuss the opportunity of transurethral resection of prostate (TURP) after transrectal prostate biopsy.Methods We analyzed 60 cases of benign prostatic hyperplasia(BPH) who underwent TURP after transrectal prostate biopsy from September 2013 to September 2015.All the patients were divided into either group A or group B in chronological order, with 30 cases in each group.There were no significant differences in age, prostate specific antigen (PSA), prostate volume, hemoglobin level, and international prostate symptom score (IPSS) between the two groups.The group A and group B were treated by TURP at 1 week and 4 weeks after transrectal prostate biopsy, respectively.The parameters including operation time, excised prostate weight, intraoperative total blood loss, bladder irrigation time, and IPSS at 3 months after operation were recorded.Results The operation time, intraoperative total blood loss, bladder irrigation time, and IPSS in the group B were significantly lower than those in the group A [(58.3±6.0) min vs.(62.0±3.3) min, t=2.952, P=0.005;(154.1±15.8) ml vs.(167.4±29.5) ml, t=2.181, P=0.035;(19.2±0.8) h vs.(20.6±2.3) h, t=3.034, P=0.004;(18.3±2.5) points vs.(20.3±2.0) points, t=3.419, P=0.001].The excised prostate weight in the group B was significantly higher than that in the group A [(37.1±4.0) g vs.(33.3±7.8) g, t=-2.341, P=0.024].Conclusions TURP performed at 4 weeks after transrectal prostate biopsy can significantly increase the excised prostate weight, reduce intraoperative total blood loss volume, shorten the operation time and postoperative bladder irrigation time, and improve urinary symptoms.In brief, we recommend that TURP be executed at 4 weeks after transrectal prostate biopsy.

Cancer metabolism and epigenetic alteration are two critical mechanisms for tumorigenesis and cancer progres?sion; however, the dynamic interplay between them remains poorly understood. As reported in the article entitled “Chromatin remodeling factor LSH drives cancer progression by suppressing the activity of fumarate hydratase,” which was recently published inCancer Research, our group examined the physiological role of lymphocyte?speciifc heli?case (LSH) in nasopharyngeal carcinoma (NPC) by focusing on cancer progression and the tricarboxylic acid cycle. We found that LSH was overexpressed in NPC, and its expression associated with Epstein?Barr virus infection. We also found that LSH directly suppressed fumarate hydratase (FH), a key component of the tricarboxylic acid cycle, in combination with euchromatic histone?lysine N?methyltransferase 2 (EHMT2), also known as G9a. Depletion of FH promoted epithelial?mesenchymal transition (EMT). Moreover, LSH controlled expression of tricarboxylic acid cycle intermediates that promote cancer progression, including EMT, through activation by inhibitor of nuclear factor kappa?B kinase alpha (IKKα), a chromatin modiifer and transcriptional activator. Our study showed that LSH plays a critical role in cancer progression, which has important implications for the development of novel strategies to treat NPC.

Gastric cancer is the fourth malignancies and the second cancer -related mortality rate in the world.Although the incidence of gastric cancer has declined in the past few decades ,it is still a serious health problem.Tumor microenvironment plays an important role in tumorigenesis and progression .The main components of gastric cancer include tumor associated macrophages、lymphocytes、cancer-associated fibroblasts、angiogenesis factors,cytokines,gastric microenvironment and the mechanism of action of chemokines .In this review,the corre-lation between tumor microenvironment and GC is discussed .

OBJECTIVETo elucidate the regulation of the phosphorylation of epidermal growth factor receptor (EGFR) by the EB virus encoded latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma cell line.

METHODSThe levels of EGFR expression and phosphorylation in pTet-on LMP1 HNE2 cell, a nasopharyngeal carcinoma (NPC) cell line, in the dynamic expression of LMP1 induced by different concentrations of doxycycline (Dox) were observed. The EGFR dominant negative mutant and LMP1 antisense expression plasmid were transiently transfected into pTet-on LMP1 HNE2 cells by lipofectamine, and the changes in EGFR phosphorylation were observed by immunocoprecitation and Western blot. The changes in EGFR phosphorylation were observed after EGF treatment.

RESULTSIn pTet-on LMP1 HNE2 cells, Dox-induced LMP1 upregulated EGFR expression and phosphorylation in a dose-dependent manner. After EGFR dominant negative mutant was transfected into pTet-on LMP1 HNE2 cells, the increase of EGFR phosphorylation was inhibited completely. When LMP1 antisense expression plasmid was transfected into pTet-on LMP1 HNE2 cells, the levels of EGFR phosphorylation were also inhibited significantly. Meanwhile, after EGF had been added into pTet-on LMP1 HNE2 cells, increase of EGFR phosphorylation was induced, but it was completely blocked by EGFR dominant negative mutant and the introduction of LMP1 antisense.

CONCLUSIONEB virus encoded LMP1 not only induces the dose-dependent expression of EGFR, but also the dose-dependent phosphorylation of EGFR. The phosporylation of EGFR may play a vital role in the development of nasopharyngeal carcinoma.

Blotting, Western ; Epidermal Growth Factor ; metabolism ; Herpesvirus 4, Human ; metabolism ; Humans ; Nasopharyngeal Neoplasms ; pathology ; virology ; Phosphorylation ; Receptor, Epidermal Growth Factor ; metabolism ; Tumor Cells, Cultured ; Viral Matrix Proteins ; metabolism