Publications by authors named "Bilan Li"

23 Publications

  • Page 1 of 1

The Preoperative Diagnostic Value of MRI and Otoneural Tests in Acoustic Neuroma.

Front Oncol 2021 29;11:626485. Epub 2021 Jun 29.

Department of Otolaryngology-Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

Objectives: To determine the preoperative diagnostic accuracy of MRI and otoneural tests (ONT) for acoustic neuroma (AN) in a cohort of unselected patients with pontocerebellar angle tumors. To find a convenient way to screening out the potential asymptomatic AN patient earlier.

Design: This diagnostic accuracy study was performed in a central hospital and included a consecutive sample of unilateral incipient pontocerebellar angle tumor patients referred for MRI and ONT before surgery. Different AN features of MRI and ONT were collected and concluded into preoperative diagnostic variables or variable combinations. Those of MRI and ONT are analyzed and compared with biopsy results by multivariable receiver operating characteristic (ROC) analysis. The early-stage group, the course of which is 1 year or less, was separately computed and compared.

Results: Eighty-three subjects were collected from June 2013 to June 2019; 62 were confirmed AN postoperatively by biopsy, whereas others are not AN. The area under the curve (AUC) of MRI was 0.611, whereas the AUC of ONT was 0.708. In the early-stage group, the AUC of MRI was 0.539, and the AUC of ONT was 0.744.

Conclusions: ONT was able to identify more subjects affected by unilateral incipient AN than MRI preoperatively. Given that ONT is a functional test for internal auditory canal nerves, it is an optimal screening test for AN patients because it provides more information than MRI for the further clinical plan. It is particularly noteworthy for identifying asymptomatic AN patients and for early stage. Therefore, it may help more patients from unnessesary surgery. Furthermore, an MRI follow-up is suggested if the patient was found alert in ONT.
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http://dx.doi.org/10.3389/fonc.2021.626485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276692PMC
June 2021

LncRNA APTR Promotes Uterine Leiomyoma Cell Proliferation by Targeting ERα to Activate the Wnt/β-Catenin Pathway.

Front Oncol 2021 10;11:536346. Epub 2021 Mar 10.

Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.

The molecular mechanisms by which uterine leiomyoma (UL) cells proliferate are unclear. Long noncoding RNA (lncRNA) is reported to participate in the occurrence and development of gynecological cancers. We investigated the molecular mechanisms that lncRNA uses in UL. We found that lncRNA Alu-mediated p21 transcriptional regulator (APTR) showed higher expression in UL tumor tissues compared with that in normal uterine tissues. APTR induced cell proliferation and colony formation both and . The JASPAR database showed that APTR was likely interacted with ERα, and these molecules were identified laser scanning confocal microscopy and RNA immunoprecipitation analysis. To verify the correlation between APTR and ERα, we overexpressed and underexpressed APTR and simultaneously expressed ERα. The results showed that APTR function was suppressed. APTR increased the expressions of the proteins in the Wnt pathway, and inhibiting ERα eliminated these responses. In conclusion, our data suggest that APTR promoted leiomyoma cell proliferation through the Wnt pathway by targeting ERα, suggesting a new role of APTR in the Wnt signaling pathway in UL.
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http://dx.doi.org/10.3389/fonc.2021.536346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989393PMC
March 2021

A Prospective Study of Sentinel Lymph Node Mapping for Endometrial Cancer: Is It Effective in High-Risk Subtypes?

Oncologist 2019 12 3;24(12):e1381-e1387. Epub 2019 Jul 3.

Departments of Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China

Background: The efficacy of sentinel lymph node (SLN) mapping for high-risk endometrial cancer remains unclear. This prompted us to evaluate the sensitivity, negative predictive value (NPV), and false-negative (FN) rate of cervical injection of indocyanine green (ICG) SLN mapping in patients with endometrial cancer.

Materials And Methods: This prospective interventional study was performed at a single university teaching hospital. Consecutive patients with early-stage endometrial cancer who underwent laparoscopic surgical staging were included. Cervical injection of ICG and near-infrared SLN identification and biopsy were performed for all study patients followed by systematic pelvic lymphadenectomy, whereas para-aortic lymphadenectomy was performed in all patients with high-risk histologies. SLN detection rates, sensitivity, NPV, and FN rates were calculated.

Results: Between July 2016 and July 2018, 131 patients were enrolled. The overall SLN detection rate was 93.1%, with a bilateral detection rate of 61.8%. Four positive SLNs were identified in four patients. Lymph node metastasis was observed in four additional patients without positive SLNs. These four patients belonged to a group of patients with a high-risk subtype. Three of the four patients had isolated para-aortic node metastases. In low-risk endometrial cancers, the sensitivity of the SLN technique to identify nodal metastatic disease was 100% (95% confidence interval [CI] 31.0-100), with an NPV and FN rate of 100% (95% CI 95.1-100) and 0%, respectively. In high-risk endometrial cancers, the sensitivity, NPV, and FN rate were 20% (95% CI 1.0-70.1), 83.3% (95% CI 61.8-94.5), and 80%, respectively.

Conclusion: Cervical injection of ICG and SLN mapping yielded a low sensitivity and a high FN rate for the identification of node metastasis in endometrial cancer with high-risk histologies.

Implications For Practice: The efficacy of sentinel lymph node (SLN) mapping for high-risk endometrial cancer remains unclear. This study enrolled 131 patients with early-stage endometrial cancer who underwent cervical injection of indocyanine green SLN mapping followed by systematic pelvic lymphadenectomy and para-aortic lymphadenectomy. The key result was that SLN mapping yielded a low sensitivity and a high false-negative rate for the identification of node metastasis in endometrial cancer with high-risk histologies. The SLN strategy in these patients may increase the risk of missed diagnosis of isolated para-aortic node metastases and seems to be unacceptable in clinical practice.
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http://dx.doi.org/10.1634/theoncologist.2019-0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975967PMC
December 2019

TRIB3 suppresses proliferation and invasion and promotes apoptosis of endometrial cancer cells by regulating the AKT signaling pathway.

Onco Targets Ther 2019 27;12:2235-2245. Epub 2019 Mar 27.

Department of Gynaecology, Shanghai First Maternity and Infant Hospital, Tongji University, Shanghai 201204, China,

Objective: The aim of this study was to examine the effect of on proliferation, apoptosis, and migration of endometrial cancer (EC) cells and explore the relationship between TRIB3 and AKT signaling pathway in EC progression.

Methods: Immunohistochemical analysis was performed to measure the expression level of TRIB3 in normal endometrium tissues and EC tissues. Overexpression and shRNA knockdown techniques were applied by transfecting EC cells (ISK and AN3CA), and the effect of TRIB3 on EC cell biological behaviors was evaluated. Cell Counting Kit-8 and colony formation assays were utilized to investigate EC cell proliferation ability, and flow cytometry was performed to assess the apoptosis of EC cells. Moreover, the migration and invasion of EC cells were detected by transwell assay, and the levels of MMP-2 and MMP-9 were measured by ELISA. Additionally, Western blot analysis was carried out to determine the levels of AKT and p-AKT.

Results: The expression level of TRIB3 was higher in EC than normal endometrium tissues, and its overexpression promoted apoptosis and suppressed proliferation of EC cells. Furthermore, TRIB3 retarded the migration and invasion of EC cells and decreased the levels of MMP-2 and MMP-9. Conversely, TRIB3 inhibition enhanced the expression levels of MMP-2 and MMP-9, and proliferation and migration of EC cells but suppressed their apoptosis. Similarly, TRIB3 overexpression reduced while its knockdown increased the level of p-AKT.

Conclusion: inhibited proliferation and migration and promoted apoptosis of EC cells probably through regulating AKT signaling pathway.
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http://dx.doi.org/10.2147/OTT.S189001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441550PMC
March 2019

DICER1 regulates endometrial carcinoma invasion via histone acetylation and methylation.

J Cancer 2017 12;8(6):933-939. Epub 2017 Mar 12.

Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University, School of Medicine, Shanghai, P.R. China.

Endometrial carcinoma (EC) is one of the most common gynecologic malignancy, but molecular mechanisms of the development and progression of EC remain unclear. Here we showed that the expression of DICER1 was negatively associated with the level of histone methylation, histone acetylation and PRC2 components SUZ12 and EZH2 in EC cells. In addition, knockdown of DICER1 significantly downregulated miR-200b and let-7i, which may then regulate their targets SUZ12 and EZH2. Furthermore, knockdown of DICER1 remarkably suppressed the expression of epithelial cell marker E-cadherin, induced the expression of mesenchymal cell marker Vimentin, and promoted the invasion of EC cells. In conclusion, our data suggest that DICER1 suppresses SUZ12 and EZH2 via affecting their upstream miRNA synthesis, and inhibits epithelial-mesenchymal transition(EMT) and invasion of EC cells via histone modification.
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http://dx.doi.org/10.7150/jca.17435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436244PMC
March 2017

DNMT1 regulates human endometrial carcinoma cell proliferation.

Onco Targets Ther 2017 29;10:1865-1873. Epub 2017 Mar 29.

Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Endometrial carcinoma (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. This study aimed to investigate the role of DNA methyltransferase 1 (DNMT1), a member of DNA methyltransferases, in EC. AN3CA cells were transfected with DNMT1 siRNA. The proliferation, cell cycle, and apoptosis of AN3CA cells were evaluated by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The expression of related genes was detected by polymerase chain reaction and Western blot analysis. Knockdown of DNMT1 inhibited the proliferation, induced apoptosis, and G0/G1 phase arrest of AN3CA cells. Furthermore, knockdown of DNMT1 upregulated the expression of nuclear factor kappa-B-inhibitor alpha (NF-κBIA) and Bax and downregulated the expression of Bcl-2 and CCND1/2 in AN3CA cells. In conclusion, this study provides the first evidence that knockdown of DNMT1 affects the expression of cell cycle- and apoptosis-associated proteins in EC cells, suggesting the potential of DNMT1 in EC therapy.
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http://dx.doi.org/10.2147/OTT.S130022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384697PMC
March 2017

Clinical characteristics of persistent ectopic pregnancy after salpingostomy and influence on ongoing pregnancy.

J Obstet Gynaecol Res 2017 Mar 26;43(3):564-570. Epub 2017 Jan 26.

Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.

Aim: The aim of this study was to assay the clinical characteristics of persistent ectopic pregnancy (PEP) and its influence on ongoing pregnancy.

Methods: We retrospectively reviewed 2498 patients who received salpingostomies as primary management for ectopic pregnancies from January 2004 to December 2009, using medical records and telephone inquiries. Clinical characteristics of the 52 patients (2.08%) who were diagnosed with PEP after salpingostomy were compared with those who received satisfactory treatment. The odds ratios and 95% confidential intervals were calculated for each variable by univariate and (for significantly different factors) multivariate analysis.

Results: Preoperatively, patients with PEP after salpingostomy significantly differed from the non-PEP patients in gestational age, mass size and pelvic adhesiolysis. Serum β-human chorionic gonadotropin levels in PEP patients were monitored after surgery, which had declined by 28.31% on postoperative day (POD) 4, 40.22% on POD 7, 51.46% on POD 10 and 53.43% on POD 21. Repeat ectopic pregnancy (REP) tended to occur more frequently in PEP patients (PEP: 5 cases, 10.20%; non-PEP: 4 cases, 2.80%; P = 0.034). Multivariate analysis showed that pelvic adhesions and PEP were the strongest independent predictors of REP.

Conclusion: Gestational age, mass size and pelvic adhesions were significantly correlated with PEP. PEP was an independent prognostic factor for REP. However, a multicenter study is needed to support and extend our findings.
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http://dx.doi.org/10.1111/jog.13251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347973PMC
March 2017

Prognostic Significance of Preoperative Prognostic Nutritional Index in Epithelial Ovarian Cancer Patients Treated with Platinum-Based Chemotherapy.

Oncol Res Treat 2016 19;39(11):712-719. Epub 2016 Oct 19.

Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.

Background: The aim of present study was to investigate the role of the prognostic nutritional index (PNI) used as a prognostic marker for predicting response and survival outcomes in patients with epithelial ovarian cancer (EOC) who are receiving platinum-based chemotherapy.

Patients And Methods: Patients with a new diagnosis of EOC receiving postoperative platinum-based chemotherapy were identified. The PNI was calculated as 10 × serum albumin value (g/dl) + 0.005 × peripheral lymphocyte count (per mm3). Patients were divided into a platinum-resistant (P-R) group and a platinum-sensitive (P-S) group according to the chemotherapeutic response. A receiver operating characteristic (ROC) curve was used to calculate the optimal cut-off value for PNI to predict chemotherapeutic response and prognosis.

Results: A total of 344 patients were enrolled. Area under the curve, sensitivity, and specificity of PIN < 45 to predict platinum resistance were: 0.688, 62.50%, and 83.47%, respectively. Patients with a lower PNI (< 45) had shorter progression-free survival (PFS) and overall survival (OS). PNI showed a significant association with PFS (hazard ratio (HR) 1.890, 95% confidence interval (CI) 1.396-2.560; p < 0.001) and OS (HR 1.747, 95% CI 1.293-2.360; p < 0.001).

Conclusion: Our results suggest that PNI assessment could assist the identification of patients with a poor prognosis and has potential clinical value in predicting platinum resistance in patients with EOC.
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http://dx.doi.org/10.1159/000452263DOI Listing
March 2017

Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are predictive of chemotherapeutic response and prognosis in epithelial ovarian cancer patients treated with platinum-based chemotherapy.

Cancer Biomark 2016 Jun;17(1):33-40

The aim of present study was to investigate the role of preoperative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) used as prognostic markers for predicting chemotherapeutic response and survival outcomes in patients with epithelial ovarian cancer (EOC) who are receiving platinum-based chemotherapy. A total of 344 patients diagnosed with EOC who are receiving platinum-based chemotherapy from 2005 to 2010 in the hospital were enrolled. NLR and PLR were calculated from complete blood cell count taken before operation. The patients were divided into platinum-resistant (P-R) group and platinum-sensitive (P-S) group according to chemotherapeutic response. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. We used receiver operating characteristic (ROC) curves to calculate optimal cut-off values for NLR and PLR to predict chemotherapeutic response and prognosis. The AUC, sensitivity, specificity of NLR > 3.02 to predict platinum resistance were 0.819, 75.0% and 81.45%, respectively. The corresponding values of PLR > 207 were 0.727, 60.42% and 85.48%, respectively. Patients with lower value of NLR (NLR < 3.02) or PLR (PLR < 207) had a longer progression-free survival (PFS) and overall survival (OS). In multivariate analysis, NLR and PLR showed a significant association with PFS (hazard ratio [HR], 1.733; 95%CI, 1.225-2.453, P = 0.002 and HR, 1.952; 95%CI, 1.430-2.662, P < 0.001) and OS (HR, 1.616; 95%CI, 1.138-2.297, P = 0.007, and HR, 2.167; 95%CI, 1.565-3.000, P < 0.001). These results suggest that the assessment of NLR and PLR could assist the identification of patients with poor prognosis and had potential clinical value in predicting platinum resistance in patients with EOC.
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http://dx.doi.org/10.3233/CBM-160614DOI Listing
June 2016

EFEMP1 is repressed by estrogen and inhibits the epithelial-mesenchymal transition via Wnt/β-catenin signaling in endometrial carcinoma.

Oncotarget 2016 May;7(18):25712-25

Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.

Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) acted as a tumor suppressor in endometrial carcinoma (EC). However, the correlation between EFEMP1 and estrogen is unknown. Here, we reported that the expression of EFEMP1 was conversely associated with ERα in endometrial carcinoma tissues. In endometrial carcinoma cells, estrogen/ERα signaling significantly suppressed the expression of EFEMP1. Moreover, chromatin immunoprecipitation (CHIP) and dual-luciferase reporter assays demonstrate that estrogen/ERα bound to the estrogen response element (ERE) located in EFEMP1 promoter and repressed its expression. Besides, in vitro and in vivo, EFEMP1 could remarkably suppress the expression of epithelial-mesenchymal transition (EMT) markers such as Vimentin, Snail and the Wnt/β-catenin target genes like Cyclin-D1 and c-Myc, which could be restored when EFEMP1 was silenced. In addition, XAV93920 (the inhibitor of the Wnt/β-catenin pathway) blocked and LiCl (the activator of the Wnt/β-catenin pathway) enhanced the effect of EFEMP1 on EMT. In conclusion, we demonstrated that estrogen/ERα signal suppresses EFEMP1. Besides, EFEMP1 inhibits EMT via interfering the Wnt/β-catenin signaling.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041938PMC
http://dx.doi.org/10.18632/oncotarget.8263DOI Listing
May 2016

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation.

Am J Physiol Lung Cell Mol Physiol 2014 Nov 12;307(10):L800-10. Epub 2014 Sep 12.

Department of Pediatrics, National Jewish Health, Denver, Colorado

ERB family receptors (EGFR, ERB-B2, ERB-B3, and ERB-B4) regulate epithelial cell function in many tissue types. In the human airway epithelium, changes in ERB receptor expression are associated with epithelial repair defects. However, the specific role(s) played by ERB receptors in repair have not been determined. We aimed to determine whether ERB receptors regulate proliferation of the tracheobronchial progenitor, the basal cell. Receptor tyrosine kinase arrays were used to evaluate ERB activity in normal and naphthalene (NA)-injured mouse trachea and in air-liquid interface cultures. Roles for epidermal growth factor (EGF), EGFR, and ERB-B2 in basal cell proliferation were evaluated in vitro. NA injury and transgenic expression of an EGFR-dominant negative (DN) receptor were used to evaluate roles for EGFR signaling in vivo. EGFR and ERB-B2 were active in normal and NA-injured trachea and were the only active ERB receptors detected in proliferating basal cells in vitro. EGF was necessary for basal cell proliferation in vitro. The EGFR inhibitor, AG1478, decreased proliferation by 99, and the Erb-B2 inhibitor, AG825, decreased proliferation by ∼66%. In vivo, EGFR-DN expression in basal cells significantly decreased basal cell proliferation after NA injury. EGF and EGFR are necessary for basal cell proliferation. The EGFR/EGFR homo- and the EGFR/ERB-B2 heterodimer account for ∼34 and 66%, respectively, of basal cell proliferation in vitro. Active EGFR is necessary for basal cell proliferation after NA injury. We conclude that EGFR activation is necessary for mouse basal cell proliferation and normal epithelial repair.
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http://dx.doi.org/10.1152/ajplung.00201.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233294PMC
November 2014

The rapid and sustained responses of dendritic cells to influenza virus infection in a non-human primate model.

Braz J Infect Dis 2014 Jul-Aug;18(4):406-13. Epub 2014 Apr 26.

Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA. Electronic address:

Dendritic cells (DCs) are readily infected by influenza viruses and play a crucial role in regulating host innate and adaptive immune responses to viral infection. The aims of this study are to characterize the dynamic changes in the numbers and maturation status of dendritic cells present in the lung and lung-associated lymph nodes (LALNs) in the model of a non-human primate (NHP) infected by influenza A virus (IAV). Cynomolgus macaques were infected with influenza A virus (H3N2) via bronchoscopy. Flow cytometry was used to analyze the DC numbers, maturation status and subsets during the time of acute infection (days 1, 2, 3, 4, 7) and the resolution phase (day 30). A dramatic increase in the numbers of influenza A virus-infected CD11c+CD14- myeloid dendritic cells (mDCs) and CD11c-CD123+ plasmacytoid dendritic cells (pDCs) were observed from day 1 to day 4 and peak up from day 7 post-infection. In lung and lung-associated lymph nodes, the numbers and maturation status of myeloid dendritic cells and plasmacytoid dendritic cells increased more slowly than those in the lung tissues. On day 30 post-infection, influenza A virus challenge increased the number of myeloid dendritic cells, but not plasmacytoid dendritic cells, compared with baseline. These findings indicate that dendritic cells are susceptible to influenza A virus infection, with the likely purpose of increasing mature myeloid dendritic cells numbers in the lung and lung and lung-associated lymph nodes, which provides important new insights into the regulation of dendritic cells in a non-human primate model.
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http://dx.doi.org/10.1016/j.bjid.2013.12.008DOI Listing
October 2014

Elevated MiR-222-3p promotes proliferation and invasion of endometrial carcinoma via targeting ERα.

PLoS One 2014 31;9(1):e87563. Epub 2014 Jan 31.

Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

MicroRNAs play key roles in tumor proliferation and invasion. Here we show distinct expression of miR-222-3p between ERα-positive and ERα-negative endometrial carcinoma (EC) cell lines and primary tumors, and investigation of its relationship with ERα and other clinical parameters. In vitro, the function of miR-222-3p was examined in RL95-2 and AN3CA cell lines. MiR-222-3p expression was negatively correlated with ERα. Over-expressed miR-222-3p in RL95-2 cells promoted cell proliferation, enhanced invasiveness and induced a G1 to S phase shift in cell cycle. Furthermore, the miR-222-3p inhibitor decreased the activity of AN3CA cells to proliferate and invade. In vivo, down-regulated miR-222-3p of AN3CA cells inhibited EC tumor growth in a mouse xenograft model. Additionally, miR-222-3p increased raloxifene resistance through suppressing ERα expression in EC cells. In conclusion, miR-222-3p plays a significant role in the regulation of ERα expression and could be potential targets for restoring ERα expression and responding to antiestrogen therapy in a subset of ECs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909214PMC
October 2014

MUC1 in macrophage: contributions to cigarette smoke-induced lung cancer.

Cancer Res 2014 Jan 26;74(2):460-70. Epub 2013 Nov 26.

Authors' Affiliations: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and Department of Physiology & Lung Center, Temple University School of Medicine, Philadelphia, Pennsylvania.

Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke increases Muc1 expression in mouse lung macrophages, where we hypothesized MUC1 may contribute to cigarette smoke-induced transformation of bronchial epithelial cells. In human macrophages, cigarette smoke extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced extracellular signal-regulated kinase (ERK) activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNA interference-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α-converting enzyme (TACE), arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE induction through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK, and MUC1 for TNF-α secretion induced by CSE from macrophages. Furthermore, our results show how MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals from macrophages.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947020PMC
January 2014

Human tracheobronchial basal cells. Normal versus remodeling/repairing phenotypes in vivo and in vitro.

Am J Respir Cell Mol Biol 2013 Dec;49(6):1127-34

1 Department of Pediatrics.

Human tracheobronchial epithelial (TBE) basal cells (BCs) function as progenitors in normal tissue. However, mechanistic studies are typically performed in vitro and frequently use BCs recovered from patients who die of nonrespiratory disease. It is not known whether the cadaveric epithelium (1) is undergoing homeostatic remodeling and/or repair, or (2) yields BC clones that represent homeostatic processes identified in tissue. We sought to compare the phenotype of TBE-BCs with that of BCs cultured under optimal clone-forming conditions. TBE pathology was evaluated using quantitative histomorphometry. The cultured BC phenotype was determined by fluorescence-activated cell sorter analysis. Clone organization and cell phenotype were determined by immunostaining. The cadaveric TBE is 20% normal. In these regions, BCs are keratin (K)-5(+) and tetraspanin CD151(+), and demonstrate a low mitotic index. In contrast, 80% of the cadaveric TBE exhibits homeostatic remodeling/repair processes. In these regions, BCs are K5(+)/K14(+), and a subset expresses tissue factor (TF). Passage 1 TBE cells are BCs that are K5(+)/TF(+), and half coexpress CD151. Optimal clone formation conditions use an irradiated NIH3T3 fibroblast feeder layer (American Type Culture Collection, Frederick, MD) and serum-supplemented Epicult-B medium (Stemcell Technologies, La Jolla, CA). The TF(+)/CD151(-) BC subpopulation is the most clonogenic BC subtype, and is enriched with K14(+) cells. TF(+)/CD151(-) BCs generate clones containing BCs that are K5(+)/Trp63(+), but K14(-)/CD151(-). TF(+) cells are limited to the clone edge. In conclusion, clonogenic human TBE BCs (1) exhibit a molecular phenotype that is a composite of the normal and remodeling/reparative BC phenotypes observed in tissue, and (2) generate organoid clones that contain phenotypically distinct BC subpopulations.
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http://dx.doi.org/10.1165/rcmb.2013-0049OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931114PMC
December 2013

Epigenetic inactivation of EFEMP1 is associated with tumor suppressive function in endometrial carcinoma.

PLoS One 2013 28;8(6):e67458. Epub 2013 Jun 28.

Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: EFEMP1, the epidermal growth factor-containing fibulin-like extracellular matrix protein 1, functions as an oncogene or a tumor suppressor depending on the cancer types. In this study, we aim to determine whether EFEMP1 affects the tumorigenesis and progression of endometrial carcinoma.

Methods: The expression of EFEMP1 was investigated using immunohistochemistry in a panel of normal endometrium (n = 40), atypical hyperplasia (n = 10) and endometrial carcinoma tissues (n = 84). Methylation status of the EFEMP1 promoter was detected by methylation-specific PCR (MSP) and bisulphite genomic sequencing. Up- or down-regulation of EFEMP1 were achieved by stable or transient transfection with pCMV6/GFP/Neo-EFEMP1 or pGPU6/GFP/Neo-shEFEMP1 respectively. Effects of EFEMP1 on tumor proliferation, invasion and migration were evaluated by MTT, plate colony formation, Transwell and wound healing assay. The nude mouse tumor xenograft assay was used to investigate function of EFEMP1 in vivo.

Results: Compared with normal endometrium (32/40) and atypical hyperplasia (7/10), EFEMP1 expression was much lower in endometrial carcinoma tissues (16/84) (P<0.001 and P = 0.02). EFEMP1 promoter was hypermethylated in endometrial carcinoma tissues (67%) as compared to normal tissue (10%) and down-regulation of EFEMP1 was associated with promoter hypermethylation. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) and/or trichostatin A (TSA) altered EFEMP1 methylation status, and restored EFEMP1 expression. Moreover, EFEMP1 decreased secretion of MMPs and inhibited tumor cell proliferation, metastasis and invasion in vitro and suppressed tumorigenesis in nude mice. Besides, EFEMP1 increased expression of E-cadherin and suppressed expression of vimentin in endometrial carcinoma.

Conclusion: EFEMP1 is a new candidate tumor suppressor gene in endometrial carcinoma, and is frequently silenced by promoter hypermethylation. It could inhibit tumor growth and invasion both in vitro and in vivo. Our findings propose that targeting EFEMP1 might offer future clinical utility in endometrial carcinoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067458PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696089PMC
April 2014

RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species.

Carcinogenesis 2013 Sep 30;34(9):2119-28. Epub 2013 Apr 30.

Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China.

Cell survival signaling is important for the malignant phenotypes of cancer cells. Although the role of receptor-interacting protein 1 (RIP1) in cell survival signaling is well documented, whether RIP1 is directly involved in cancer development has never been studied. In this report, we found that RIP1 expression is substantially increased in human non-small cell lung cancer and mouse lung tumor tissues. RIP1 expression was remarkably increased in cigarette smoke-exposed mouse lung. In human bronchial epithelial cells (HBECs), RIP1 was significantly induced by cigarette smoke extract or benzo[a]pyrene diol epoxide (BPDE), the active form of the tobacco-specific carcinogen benzo(a)pyrene. In RIP1 knockdown HBECs, BPDE-induced cytotoxicity was significantly increased, which was associated with induction of cellular reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs), including c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38. Scavenging ROS suppressed BPDE-induced MAPK activation and inhibiting ROS or MAPKs substantially blocked BPDE-induced cytotoxicity, suggesting ROS-mediated MAPK activation is involved in BPDE-induced cell death. The ROS-reducing enzyme catalase is destabilized in an ERK- and JNK-dependent manner in RIP1 knockdown HBECs and application of catalase effectively blocked BPDE-induced ROS accumulation and cytotoxicity. Importantly, BPDE-induced transformation of HBECs was significantly reduced when RIP1 expression was suppressed. Altogether, these results strongly suggest an oncogenic role for RIP1, which promotes malignant transformation through protecting DNA-damaged cells against carcinogen-induced cytotoxicity associated with excessive ROS production.
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http://dx.doi.org/10.1093/carcin/bgt143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765041PMC
September 2013

WWOX induces apoptosis and inhibits proliferation in cervical cancer and cell lines.

Int J Mol Med 2013 May 21;31(5):1139-47. Epub 2013 Mar 21.

Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital of China Welfare Institute affiliated with Shanghai Jiao Tong University, Shanghai 200032, P.R. China.

Cervical cancer is the second most common gynecological malignancy, but the molecular events involved in its development remain unclear. The tumor‑suppressor gene, WW domain-containing oxidoreductase (WWOX), has been found to be lost in various types of cancers. Few studies have been reported detailing the function of WWOX in human cervical cancer; therefore we aimed to investigate the role played by WWOX in human cervical cancer. Immunohistochemistry was used to study preinvasive and invasive primary cervical cancer. Full length cDNA was transfected into HeLa cells to overexpress WWOX, and short hairpin RNA (shRNA) was transfected into SiHa cells to deplete its expression, respectively. The cellular levels of WWOX RNA and protein were detected by real-time PCR and western immunoblotting. Proliferation rates were assessed by methyl thiazolyl tetrazolium (MTT), plate colony formation and soft agar colony assays. Cellular apoptosis was measured by flow cytometry and TdT-mediated dUTP nick-end labeling (TUNEL) assay. The activity of caspase-3 and its protein levels were determined by caspase-3 activity assay and western blot analysis. Xenografts were established by injecting cells into nude mice. The results showed that WWOX expression was decreased in human cervical cancer and cervical cancer cell lines. Reconstitution of WWOX in HeLa cells inhibited their proliferation and induced apoptosis, while knockdown of WWOX in SiHa cells promoted proliferation and inhibited apoptosis. Xenografts in groups of mice verified the effect in vivo. These data suggest that underexpression of WWOX is associated with cervical cancer development. Modulation of WWOX expression may be an effective and novel method for the treatment of cervical cancer.
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http://dx.doi.org/10.3892/ijmm.2013.1314DOI Listing
May 2013

β-catenin dosage is a critical determinant of tracheal basal cell fate determination.

Am J Pathol 2011 Jul 5;179(1):367-79. Epub 2011 May 5.

Department of Pediatrics, National Jewish Health, Denver, CO80206, USA.

The purpose of this study was to determine whether β-catenin regulates basal cell fate determination in the mouse trachea. Analysis of TOPGal transgene reporter activity and Wnt/β-catenin pathway gene expression suggested a role for β-catenin in basal cell proliferation and differentiation after naphthalene-mediated Clara-like and ciliated cell depletion. However, these basal cell activities occurred simultaneously, limiting precise determination of the role(s) played by β-catenin. This issue was overcome by analysis of β-catenin signaling in tracheal air-liquid interface cultures. The cultures could be divided into two phases: basal cell proliferation and basal cell differentiation. A role for β-catenin in basal cell proliferation was indicated by activation of the TOPGal transgene on proliferation days 3 to 5 and by transient expression of Myc (alias c-myc). Another peak of TOPGal transgene activity was detected on differentiation days 2 to 10 and was associated with the expression of Axin 2. These results suggest a role for β-catenin in basal to ciliated and basal to Clara-like cell differentiation. Genetic stabilization of β-catenin in basal cells shortened the period of basal cell proliferation but had a minor effect on this process. Persistent β-catenin signaling regulated basal cell fate by driving the generation of ciliated cells and preventing the production of Clara-like cells.
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http://dx.doi.org/10.1016/j.ajpath.2011.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123883PMC
July 2011

MALDI imaging MS of phospholipids in the mouse lung.

J Lipid Res 2011 Aug 20;52(8):1551-60. Epub 2011 Apr 20.

Department of Pharmacology, University of Colorado Denver, 12801 East 17 Avenue, Mail Stop 8303, Aurora, CO 80045, USA.

Lipid mediators are important in lung biochemistry and are derived from the enzymatic oxidation of arachidonic and docosahexaenoic acids, which are PUFAs that are present in phospholipids in cell membranes. In this study, MALDI imaging MS was used to determine the localization of arachidonate- and docosahexaenoate-containing phospholipids in mouse lung. These PUFA-containing phospholipids were determined to be uniquely abundant at the lining of small and large airways, which were unequivocally identified by immunohistochemistry. In addition, it was found that the blood vessels present in the lung were characterized by sphingomyelin molecular species, and lung surfactant phospholipids appeared evenly distributed throughout the lung parenchyma, indicating alveolar localization. This technique revealed unexpected high concentrations of arachidonate- and docosahexaenoate-containing phospholipids lining the airways in pulmonary tissue, which could serve as precursors of lipid mediators affecting airways biology.
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http://dx.doi.org/10.1194/jlr.M015750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137021PMC
August 2011

Context-dependent differentiation of multipotential keratin 14-expressing tracheal basal cells.

Am J Respir Cell Mol Biol 2011 Aug 3;45(2):403-10. Epub 2010 Dec 3.

Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.

Multipotential (MP) differentiation is one characteristic of a tissue-specific stem cell (TSC). Lineage tracing of tracheobronchial basal cells after naphthalene (NA) injury or in the postnatal period demonstrated that basal cells were MP progenitors for Clara-like and ciliated cells. These studies, as well as reports of spatially restricted, label-retaining basal cells, and MP differentiation by human bronchial cells support the hypothesis that a TSC maintained and repaired the tracheobronchial epithelium. However, differences in basal cell phenotype (keratin [K] 5+ versus K14+), age (postnatal versus adult), health status (normal versus injured), and injury type (acid, detergent, NA) limited comparisons among studies and thus diminished the strength of the TSC argument. The finding that K14 was up-regulated after NA injury was a caveat to our previous analysis of reparative (r)K14-expressing cells (EC). Thus, the present study lineage traced steady-state (s)K14EC and evaluated differentiation potential in the normal and repairing epithelium. We showed that sK14EC were unipotential in the normal epithelium and MP after NA, sK14EC-dervied clones were not restricted to putative TSC niches, sK14EC cells were a direct progenitor for Clara-like and ciliated cells, MP-sK14EC clones accumulated over time, and sK14EC-derived Clara-like cells were progenitors for ciliated cells.
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http://dx.doi.org/10.1165/rcmb.2010-0283OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175566PMC
August 2011

A single cell functions as a tissue-specific stem cell and the in vitro niche-forming cell.

Am J Respir Cell Mol Biol 2011 Sep 3;45(3):459-69. Epub 2010 Dec 3.

Department of Pediatrics, National Jewish Health Denver, CO, USA.

Tissue-specific stem cell (TSC) behavior is determined by the stem cell niche. However, delineation of the TSC-niche interaction requires purification of both entities. We reasoned that the niche could be defined by the location of the TSC. We demonstrate that a single CD49f(bright)/Sca1(+)/ALDH(+) basal cell generates rare label-retaining cells and abundant label-diluting cells. Label-retaining and label-diluting cells were located in the rimmed domain of a unique clone type, the rimmed clone. The TSC property of self-renewal was tested by serial passage at clonal density and analysis of clone-forming cell frequency. A single clone could be passaged up to five times and formed only rimmed clones. Thus, rimmed clone formation was a cell-intrinsic property. Differentiation potential was evaluated in air-liquid interface cultures. Homogenous cultures of rimmed clones were highly mitotic but were refractory to standard differentiation signals. However, rimmed clones that were cocultured with unfractionated tracheal cells generated each of the cell types found in the tracheal epithelium. Thus, the default niche is promitotic: Multipotential differentiation requires adaptation of the niche. Because lung TSCs are typically evaluated after injury, the behavior of CD49f(bright)/Sca1(+)/ALDH(+) cells was tested in normal and naphthalene-treated mice. These cells were mitotically active in the normal and repaired epithelium, their proliferation rate increased in response to injury, and they retained label for 34 days. We conclude that the CD49f(bright)/Sca1(+)/ALDH(+) tracheal basal cell is a TSC, that it generates its own niche in vitro, and that it participates in tracheal epithelial homeostasis and repair.
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http://dx.doi.org/10.1165/rcmb.2010-0314OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175586PMC
September 2011

Computational prediction of novel components of lung transcriptional networks.

Bioinformatics 2007 Jan 18;23(1):21-9. Epub 2006 Oct 18.

Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr SE, Albuquerque, NM 87108, USA.

Motivation: Little is known regarding the transcriptional mechanisms involved in forming and maintaining epithelial cell lineages of the mammalian respiratory tract.

Results: Herein, a motif discovery approach was used to identify novel transcriptional regulators in the lung using genes previously found to be regulated by Foxa2 or Wnt signaling pathways. A human-mouse comparison of both novel and known motifs was also performed. Some of the factors and families identified here were previously shown to be involved epithelial cell differentiation (ETS family, HES-1 and MEIS-1), and ciliogenesis (RFX family), but have never been characterized in lung epithelia. Other unidentified over-represented motifs suggest the existence of novel mammalian lung transcription factors. Of the fraction of motifs examined we describe 25 transcription factor family predictions for lung. Fifteen novel factors were shown here to be expressed in mouse lung, and/or human bronchial or distal lung epithelial tissues or lung epithelial cell lineages.

Availability: DME: http://rulai.cshl.edu/dme. MATCOMPARE: http://rulai.cshl.edu/MatCompare. MOTIFCLASS is available from the authors.
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http://dx.doi.org/10.1093/bioinformatics/btl531DOI Listing
January 2007
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