Publications by authors named "Xuyong Lin"

32 Publications

WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression.

Cell Death Dis 2021 Apr 9;12(4):384. Epub 2021 Apr 9.

Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital of China Medical University, Shenyang, China.

WW domain binding protein-2 (WBP2) can function as a Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) co-activator and has a crucial role in promoting breast cancer progression. However, the expression and potential molecular mechanisms of WBP2 in the context of lung cancer are not fully understood. We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the advanced pTNM stage, lymph node metastasis, and poor prognosis of patients. In addition, gain- and loss-of-function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 (WW and C2 domain-containing-3) with LATS1 (Large tumor suppressor-1) through its PPxY motifs, thus inhibiting the formation of the WWC3-LATS1 complex, reducing the phosphorylation level of LATS1, suppressing the activity of the Hippo pathway, and ultimately promoting YAP nuclear translocation. Therefore, from the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
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http://dx.doi.org/10.1038/s41419-021-03600-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035140PMC
April 2021

The epithelioid gastrointestinal stromal tumor with pulmonary metastasis: A rare case report and literature review.

Medicine (Baltimore) 2020 Feb;99(9):e19346

Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Rationale: Available literature states that the histological subtype of the gastrointestinal stromal tumor (GIST) with pulmonary metastasis is often spindle cell type. To our knowledge, this is the first report of the GIST with pulmonary metastasis of very uncommon epithelioid subtype.

Patient Concerns: We report a 63-year-old male presenting with the symptom of bloodstained sputum without obvious inducement. The patient had no chest pain, low back pain, fatigue, fever or night sweats symptoms.

Diagnoses: Combined chest digital radiography and the history of the patient who presented with the colon GIST of the epithelioid subtype two years ago that the mass may be a metastasis tumor. Combined with morphological and immunohistochemical staining results, a pathological diagnosis of the GIST with pulmonary metastasis was considered.

Interventions: Right lobectomy and partial upper lobectomy were performed.

Outcomes: The patient had not experienced any noticeable symptom and recurrent tumors at 6 months follow-up.

Lessons: We report a rare case of the GIST with pulmonary metastasis of epithelioid subtype. This case is of great significance to the pathologist's clinical work. For pathologists, if an epithelioid tumor in the lung is found, it is necessary to check whether the gastrointestinal tract also has the tumor, which may be an epithelioid GIST with pulmonary metastasis.
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http://dx.doi.org/10.1097/MD.0000000000019346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478712PMC
February 2020

Genomic Alterations In Primary Cardiac Diffuse Large B Cell Lymphoma: A Case Report And Literature Review.

Onco Targets Ther 2019 4;12:9085-9092. Epub 2019 Nov 4.

Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.

Primary cardiac diffuse large B cell lymphoma (PC-DLBCL) is a rare kind of hematological malignancy, and its clinical and pathologic characteristics, especially in Eastern countries, remain unclear. Moreover, genomic alterations in PC-DLBCL have not been studied previously. We describe a case of a 57-year-old man who presented with exertional dyspnoea due to a heart mass in April 2018 and was diagnosed with PC-DLBCL characterized by immunohistochemical markers of the activated B cell (ABC) subtype and double expression of c-MYC and Bcl-2. Mutations in a total of 11 genes-, and -were detected via next-generation sequencing (NGS), while 19 copy number variations (CNVs) such as 1q+, 3p+, 3q+(*2), 5p+, 6p-, 6q-, 7q+, +11, 12q-, 15q-, 17q+, 17p-, +18, 19q+, 19p-, 19q-, X q+, and -Y and 4 copy-neutral loss of heterozygosity (CN-LOH) lesions located at 1q21.1q44, 3p26.3q11.2, 3q13.11q29 and 6p22.2p21.32 were identified by single nucleotide polymorphism (SNP) array karyotyping. Some key gene alterations in lymphoma, such as deletion and amplification, were identified using SNP array analysis. The patient received 6 courses of chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, R-CHOP regimen) after surgery and is currently in remission. In summary, the present case was diagnosed as PC-DLBCL, ABC subtype by the Hans algorithm and double expression lymphoma, with co-occurrence of the and mutations (MCD) subtype by genetic alteration analysis. This study presents a unique PC-DLBCL case in which complex genomic alterations were revealed by NGS and SNP array analysis, which has never been reported in the literature, and these findings could provide new insight into the genomic characterization of PC-DLBCL.
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http://dx.doi.org/10.2147/OTT.S227122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839572PMC
November 2019

ZNFX1 anti-sense RNA 1 promotes the tumorigenesis of prostate cancer by regulating c-Myc expression via a regulatory network of competing endogenous RNAs.

Cell Mol Life Sci 2020 Mar 18;77(6):1135-1152. Epub 2019 Jul 18.

Department of Urology, First Hospital of China Medical University, Shenyang, 110001, China.

ZNFX1 anti-sense RNA 1 (ZFAS1) has been indicated in the tumorigenesis of various human cancers. However, the role of ZFAS1 in prostate cancer (PCa) progression and the underlying mechanisms remain incompletely understood. In the present study, we discovered that ZFAS1 is upregulated in PCa and that ZFAS1 overexpression predicted poor clinical outcomes. ZFAS1 overexpression notably promoted the proliferation, invasion, and epithelial-mesenchymal transition of PCa cells. Furthermore, we not only discovered that miR-27a/15a/16 are targeted by ZFAS1, which binds to their miRNA-response elements, but also revealed their tumor suppressor roles in PCa. We also identified that the Hippo pathway transducer YAP1, as well as its cooperator, TEAD1, are common downstream targets of miR-27a/15a/16. In addition, H3K9 demethylase KDM3A was found to be another target gene of miR-27a. Importantly, YAP1, TEAD1, and KDM3A all act as strong c-Myc inducers in an androgen-independent manner. Taken together, we suggest a regulatory network in which ZFAS1 is capable of enhancing c-Myc expression by inducing the expression of YAP1, TEAD1, and KDM3A through crosstalk with their upstream miRNAs, thereby globally promoting prostate cancer tumorigenesis.
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http://dx.doi.org/10.1007/s00018-019-03226-xDOI Listing
March 2020

Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance Induced by Membranous/Cytoplasmic/Nuclear Translocation of Epidermal Growth Factor Receptor.

J Thorac Oncol 2019 10 19;14(10):1766-1783. Epub 2019 Jun 19.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China. Electronic address:

Introduction: The molecular mechanism underlying the induction of resistance to tyrosine kinase inhibitors (TKIs) via the membranous/cytoplasmic/nuclear translocation of EGFR has not yet been reported.

Methods: We performed immunohistochemistry to detect the distribution of EGFR in lung adenocarcinoma specimens after TKI treatment and analyzed the relationship between different EGFR locations and patient survival duration. Mass spectrometry analysis and immunoprecipitation were performed to show the interaction of cytosolic EGFR with YY1 associated protein 1 (YAP) and salt inducible kinase 2 (SIK2). Dual-luciferase assays, immunoblotting, real-time polymerase chain reaction, and functional experiments were used to elucidate the role of EGFR cytoplasmic/nuclear translocation in Hippo pathway dysregulation.

Results: Patients with advanced lung adenocarcinoma with membranous mutant EGFR (19del or 21 L858R) showed significantly longer progression-free survival than those with cytoplasmic mutant EGFR after gefitinib treatment. The concentration that inhibits 50% in PC-9 with cytoplasmic EGFR was higher than that in hunman non-small cell lung cancer 827 with membranous EGFR. During first-generation TKI resistance induction, membrane EGFR translocated to the cytoplasm/nucleus, accompanied by the Hippo pathway inhibition. Cytoplasmic EGFR and SIK2 interaction inhibited large tumor suppressor kinase 1 (LATS1) and macrophage stimulating 1 (MST1) interaction, promoting YAP nuclear translocation. However, cells with osimertinib-induced resistance also showed EGFR translocation and lower phospho-EGF receptor but did not show Hippo pathway inhibition. Moreover, osimertinib and erlotinib could restore sensitivity to each other in resistant cells.

Conclusions: Plasma/nuclear translocation of EGFR and inhibition of the Hippo pathway are some of the important mechanisms underlying the resistance induced by first-generation TKIs. Membrane/plasma translocation of EGFR induced by osimertinib may be another resistance phenomenon besides MNNG HOS transforming gene (c-MET) amplification, C797S mutation, and ERK pathway inhibition.
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http://dx.doi.org/10.1016/j.jtho.2019.06.014DOI Listing
October 2019

USP13 functions as a tumor suppressor by blocking the NF-kB-mediated PTEN downregulation in human bladder cancer.

J Exp Clin Cancer Res 2019 Jun 14;38(1):259. Epub 2019 Jun 14.

Department of Urology, First hospital of China Medical University, No.155 Nanjing north Road, Shenyang, 110001, Liaoning, China.

Background: USP13 has been reported to be involved in the tumorigenesis of human cancers, however, its functional role and regulatory mechanisms in bladder cancer (BC) remain unclear.

Methods: q-RT-PCR was performed to examine the expression of miR-130b-3p, miR-301b-3p and USP13 in BC tissue samples. Western blot, q-RT-PCR, bioinformatic analysis and dual-luciferase reporter assay were conducted to identify the regulatory function of miR-130b-3p/301b-3p for USP13. Co-immunoprecipitation assay was performed to assess the interaction between USP13 and PTEN protein. Cell-counting-kit 8, colony formation assay and transwell assay were performed to value the proliferative, migrative and invasive capacities of BC cells in vitro. Mouse xenograft model of BC cells was established to verify the function of USP13 in vivo. Immunohistochemistry was performed to identify the protein expression of USP13, NF-kB p65 or PTEN in clinical/xenograft tumor tissues.

Results: Our present study reveals that USP13 functions as a tumor suppressor by interacting with PTEN protein and increasing its expression in bladder cancer. We found that loss of USP13 led to the downregulation of PTEN and promoted proliferative, invasive and migrative capacities of bladder cancer cells. Furthermore, we discovered that USP13 was a common target of miR-130b-3p and miR-301b-3p, and the miR-130b/301b cluster, which could be transcriptionally upregulated by NF-kB. Our data demonstrated that NF-kB activation decreased expression level of USP13 and PTEN, and promoted the tumorigenesis phenotypes of BC cells. In addition, reintroduction of USP13 partially rescued PTEN expression as well as the oncogenesis trend caused by NF-kB.

Conclusion: We reported a potential regulatory loop that the NF-kB-induced miR-130b/301b overexpression decreased USP13 expression and subsequently resulted in the downregulation of PTEN protein and promoted tumorigenesis of bladder cancer. Moreover, NF-kB-mediated PTEN downregulation is very likely to facilitate the full activation of NF-kB.
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http://dx.doi.org/10.1186/s13046-019-1262-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570860PMC
June 2019

FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells.

Cancer Manag Res 2019 18;11:3395-3410. Epub 2019 Apr 18.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.

The expression of FERM-domain-containing protein-1 (FRMPD1)/FERM and PDZ domain-containing protein-2 (FRMD2) in malignant tumors, including lung cancer, and its underlying molecular mechanism have not been reported yet. Immunohistochemistry was performed to analyze the expression of FRMPD1 in lung cancer tissues, and statistical analysis was applied to analyze the relationship between FRMPD1 expression and clinicopathological factors. The biological effects of FRMPD1 on lung cancer cell proliferation and invasion were determined by functional experiments both in vivo and in vitro. Immunoblotting, RT-qPCR, dual-luciferase assay, and immunofluorescence were performed to demonstrate whether FRMPD1 stimulates Hippo signaling. Co-immunoprecipitation assays were used to clarify the underlying role of FRMPD1 in Hippo pathway activation via interaction with WW and C2 domain containing protein-3 (WWC3). We found that FRMPD1 expression in lung cancer specimens was lower than that in normal bronchial epithelium and normal submucosal glands. FRMPD1 expression had a negative correlation with age, Tumor-Node-Metastasis (TNM) stage, lymph node metastasis, as well as poor prognosis. Moreover, ectopic expression of FRMPD1 significantly inhibited the proliferation and invasion of lung cancer cells, and inhibition of FRMPD1 expression led to opposite effects. Mechanistically, we found that FRMPD1 interacted with the C-terminal PDZ binding motif of WWC3 via its PSD95/DLG/ZO1 (PDZ) domain and promoted the phosphorylation of large tumor suppressor-1 (LATS1), thus inhibiting the nuclear translocation of yes-associated protein (YAP). FRMPD1 could activate the Hippo pathway and ultimately inhibit the malignant behavior of lung cancer cells through its interaction with WWC3. This work will provide an important experimental basis for the discovery of novel biomarkers of lung cancer and the development of targeted drugs.
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http://dx.doi.org/10.2147/CMAR.S194512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497479PMC
April 2019

CCDC85B promotes non-small cell lung cancer cell proliferation and invasion.

Mol Carcinog 2019 01 9;58(1):126-134. Epub 2018 Oct 9.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3β phosphorylation and upregulated the levels of active β-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B-induced upregulation of phosphorylated GSK3β and active β-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3β/β-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment.
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http://dx.doi.org/10.1002/mc.22914DOI Listing
January 2019

WWC3 inhibits epithelial-mesenchymal transition of lung cancer by activating Hippo-YAP signaling.

Onco Targets Ther 2018 8;11:2581-2591. Epub 2018 May 8.

Department of Pathology, College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.

Background: Though we recently reported that the WWC3 inhibits the invasiveness and metastasis of lung cancer by activating the Hippo pathway, the impact and underlying mechanisms of this process still remain unclear.

Methods: To identify the role of WWC3 in epithelial-mesenchymal transition of lung cancer, we performed immunohistochemistry to detect the expression levels of WWC3 and EMT-related biomarker, and analyzed their correlations in a cohort of 127 patients with NSCLC. Wound healing assay and cell invasion assay were applied to explore cell invasive ability change after WWC3 knockdown. qRT-PCR and immunoblotting were performed to assess mRNA and protein levels of EMT-related biomarkers and the main molecules changes of Hippo signaling caused by WWC3. Immunoprecipition was to examine WWC3 and LATS1 interaction.

Results: WWC3 knockdown drives a pronounced shift from the epithelial to the mesenchymal phenotype in lung cancer cells. In addition, WWC3 ectopic expression in lung cancer cells attenuates mesenchymal markers and increases the epithelial markers expressions; however, WWC3-ΔWW plasmid abrogated these effects. WWC3 silencing by shRNA exerts the opposite effect. Furthermore, WWC3 levels were inversely correlated with the levels of EMT inducers (Snail and Slug) in lung cancer cells and specimens. Immunoblotting revealed that WWC3 wild-type upregulates large tumor suppressor (LATS1) and yes-associated protein (YAP) phosphorylation through its WW domain, hence activating Hippo pathway. Knockdown of YAP and LATS1, as well as the as the Verteporfin (VP) usage, could reverse this effect caused by WWC3 silencing.

Conclusion: These findings suggest that WWC3 works as a tumor suppressor to inhibit EMT process and confer its candidacy as a potential therapeutic target in lung cancer.
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http://dx.doi.org/10.2147/OTT.S162387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951220PMC
May 2018

Protein kinase C-α (PKCα) modulates cell apoptosis by stimulating nuclear translocation of NF-kappa-B p65 in urothelial cell carcinoma of the bladder.

BMC Cancer 2017 Jun 19;17(1):432. Epub 2017 Jun 19.

Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China.

Background: The protein kinase C (PKC) family comprises central regulators of multiple signal transduction processes and is involved in the progression of many cancers. Nuclear factor Kappa-B (NF-κB) is constitutively expressed in cancer tissues and stimulates the transcription of various tumor-related genes. The present study aims to investigate the clinical significance of PKCα and NF-κB p65 in bladder cancer tissues and the mechanism underlying PKCα induction of bladder cancer cell apoptotic resistance through stimulation of p65 nuclear translocation.

Methods: Expression of PKCα and NF-κB subunit p65 was detected in seven bladder cancer cell lines by western blot and in 30 bladder cancer tissue specimens by immunostaining. Immunofluorescence was performed to evaluate p65 nuclear translocation induced by Phorbol 12-myristate 13-acetate (PMA). PKCα/β selective inhibitor Gö6976, PKC pan-inhibitor sotrastaurin, and the PKC siRNA were employed to conduct PKC inhibition/knockdown in bladder cancer cells. Luciferase reporter assays were performed to measure the activity of NF-κB. Flow cytometry and TUNEL analysis were used to assess cell apoptosis.

Results: Expression of PKCα and NF-κB was found to positively correlate with tumor progression in 30 tumor tissue specimens. Furthermore, a Pearson's correlation coefficient analysis revealed a positive correlation between PKCα and NF-κB expression. Among the PKC inhibitors, the PKCα/β selective inhibitor Gö6976 yielded the most significant block of PKCα and NF-κB activation by PMA. Knockdown of NF-κB p65 remarkably induced cell apoptosis, but PMA restored p65 expression and significantly suppressed cell apoptosis that was otherwise induced by the p65 knockdown alone.

Conclusion: Our study showed that PKCα modulated cell resistance to apoptosis by stimulating NF-κB activation and thus promoted the tumorigenesis of bladder cancer.
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http://dx.doi.org/10.1186/s12885-017-3401-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477139PMC
June 2017

WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis.

J Pathol 2017 08 29;242(4):435-447. Epub 2017 Jun 29.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, PR China.

The scaffolding protein WWC (WW and C2-domain containing) family is known to regulate cell proliferation and organ size via the Hippo signalling pathway. However, the expression level of WWC3 in human tumours and the mechanisms underlying its role in cellular signal transduction have not yet been reported. Herein, we explored the potential roles of WWC3 in lung cancer cells and the corresponding molecular mechanisms. We found low WWC3 expression in both lung cancer cell lines and lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients with lung cancer. Moreover, the overexpression of WWC3 inhibited the proliferation and invasiveness of lung cancer cells. These effects were mediated by the inhibition and stimulation of the Wnt and Hippo pathways, respectively, in vitro and in vivo. Specifically, WWC3 interacts with Dishevelled (Dvl) proteins, prevents casein kinase 1ϵ from phosphorylating Dvls, and inhibits β-catenin nuclear translocation to inhibit the Wnt pathway. Deleting the WW and C-terminal PDZ-binding domains of WWC3 abrogated these effects. Moreover, the interaction of WWC3 with Dvls reduced the interaction between WWC3 and large tumour suppressor 1 (LATS1), as well as decreasing LATS1 phosphorylation to increase the nuclear importation of yes-associated protein (YAP) and attenuate the Hippo pathway. Deleting the WW domain of WWC3 abrogated this effect. These findings demonstrate the molecular interplay between WWC3, Dvls, and LATS1, and reveal a link between the Wnt and Hippo pathways, which provides a potential target for clinical intervention in lung cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4919DOI Listing
August 2017

NF-κB suppresses apoptosis and promotes bladder cancer cell proliferation by upregulating survivin expression in vitro and in vivo.

Sci Rep 2017 01 31;7:40723. Epub 2017 Jan 31.

Department of Urology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China.

Nuclear factor kappa-B (NF-κB) activation is a common phenomenon in cancers, which results in the aberrant expression of NF-κB target genes and leads to malignant transformation, metastatic dissemination, abnormal cell proliferation or resistance to cell death. Survivin is a unique member of the IAP family, a well-known cancer-specific molecule and a molecular marker of poor clinical outcome in several cancer types, including bladder cancer. YM-155, a potent survivin suppressor, has been shown to have anti-tumor activity in preclinical cell lines, xenograft models and phase I/II studies. In the present study, we investigated the function of the NF-κB/survivin pathway in bladder cancer. We found that NF-κB can promote cell cycle progression and reduce apoptosis by upregulating survivin expression, thereby increasing cellular proliferation. We further confirmed the tumorigenic function of the NF-κB/survivin pathway in vivo using a xenograft tumor model of stable NF-κB-overexpressing 5637 cells. Moreover, we found that YM-155 significantly induced apoptosis and decreased cellular proliferation as well as tumor growth in mice. Our results demonstrate the carcinogenic function of the NF-κB/survivin pathway in bladder cancer and the role of YM-155 as a promising agent for the strategic treatment of bladder cancer.
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http://dx.doi.org/10.1038/srep40723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282527PMC
January 2017

Rac3 regulates cell proliferation through cell cycle pathway and predicts prognosis in lung adenocarcinoma.

Tumour Biol 2016 Sep 11;37(9):12597-12607. Epub 2016 Jul 11.

Department of Thoracic Surgery, First Hospital of China Medical University, 155 Nanjingbei Street, Shenyang, Liaoning, 110001, China.

Lung cancer is still the leading cause of malignant deaths in the world. It is of great importance to find novel functional genes for the tumorigenesis of lung cancer. We demonstrated that Rac3 could promote cell proliferation and inhibit apoptosis in lung adenocarcinoma cell line A549 previously. The aim of this study was to investigate the function and mechanism of Rac3 in lung adenocarcinoma cell lines. Immunohistochemistry staining was performed in 107 lung adenocarcinoma tissues and matched non-tumor tissues. Multivariate analysis and Kaplan-Meier analysis were used to investigate the correlation between Rac3 expression and the clinical outcomes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry analysis were employed to determine the proliferative ability, cell cycle distribution, and apoptosis in H1299 and H1975 cell lines. Gene expression microarray and pathway analysis between the Rac3-siRNA group and the control group in A549 cells were performed to investigate the pathways and mechanism of Rac3 regulation. Rac3 was shown to be positively expressed in lung adenocarcinoma tissues, and the expression of Rac3 associates with longer survival in lung adenocarcinoma patients. Silencing of Rac3 significantly induced cell growth inhibition, colony formation decrease, cell cycle arrest, and apoptosis of lung adenocarcinoma cell lines, which accompanied by obvious downregulation of CCND1, MYC, and TFDP1 of cell cycle pathway involving in the tumorigenesis of lung adenocarcinoma based on the gene expression microarray. In conclusion, these findings suggest that Rac3 has the potential of being a therapeutic target for lung adenocarcinoma.
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http://dx.doi.org/10.1007/s13277-016-5126-7DOI Listing
September 2016

A subcutaneous pleomorphic hyalinizing angiectatic tumor of soft parts of the right chest wall: report of a rare case.

Int J Clin Exp Pathol 2015 1;8(9):11804-8. Epub 2015 Sep 1.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University Shenyang 110001, Liaoning, China ; Institute of Pathology and Pathophysiology, China Medical University Shenyang 110001, Liaoning, China.

Pleomorphic hyalinizing angiectatic tumor of the soft parts is an extremely rare mesenchymal tumor consisting of spindled and pleomorphic tumor cells and clusters of ectatic, fibrin-lined vessels. It typically occurs in the subcutaneous tissues of the distal extremities, usually the ankles and feet. Here we present a case of pleomorphic hyalinizing angiectatic tumor of the soft parts of the right chest wall in a 51-year old female. The tumor was subcutaneous, nonencapsulated, and about 2.0 cm×1.0 cm. Microscopically, the tumor was composed of numerous ectatic, fibrin-filled, thin-walled blood vessels, surrounded by spindled or pleomorphic tumor cells arranged in sheet-like or fascicular architecture, or randomly. Mitotic activity of the tumor cells was low. Immunohistochemical analysis shows that the tumor cells were positive for CD34 and vimentin, but negative for CD31, CK, desmin, EMA, HMB45, Myo D1, P63 and S-100. Ki67 index was about 1%.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637746PMC
September 2016

Clear cell sarcoma of soft tissue in right parapharyngeal region: report of a rare case.

Int J Clin Exp Pathol 2015 1;8(9):10935-40. Epub 2015 Sep 1.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University Shenyang 110001, China ; Institute of Pathology and Pathophysiology, China Medical University Shenyang 110001, China.

Clear cell sarcoma (CCS), initially named malignant melanoma of soft parts, is a rare malignant neoplasm typically involving deep soft tissue of the extremities, in close proximity to tendons and aponeuroses. Here we describe a case of clear cell sarcoma of the right parapharyngeal region in a young female aged 20 years. MRI detected a mass about 4.4 cm×3.4 cm×3.0 cm, located in the right parapharyngeal area and between the external pterygoid and the medial pterygoid. Microscopically, most of the tumor cells were epithelioid with palely eocinophilic cytoplasm arranged in sheets. Pleophorism of tumor cells were not marked. Immunohistochemical analysis shows that the tumor cells were positive for vimentin, S-100, HMB45 and MelanA, and negative for AE1/AE3, actin-sm, desmin, CD117, TFE-3, and P63. Ki67 index was about 5%.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637625PMC
September 2016

Cytosolic TMEM88 promotes invasion and metastasis in lung cancer cells by binding DVLS.

Cancer Res 2015 Nov 10;75(21):4527-37. Epub 2015 Sep 10.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Transmembrane protein 88 (TMEM88) is a transmembrane protein that plays a crucial role in regulating human stem cell differentiation and embryonic development. However, its expression and clinicopathologic significance in human neoplasms is unclear. In this study, the expression and subcellular localizations of TMEM88 were assessed in 214 cases of non-small cell lung cancer (NSCLC). Notably, TMEM88 was highly expressed in the cytosol of ∼60% NSCLC specimens examined. Higher expression of cytosolic TMEM88 in NSCLC correlated significantly with poor differentiation, high TNM stage, lymph node metastasis, and inferior survival. In NSCLC cells displaying membrane-localized TMEM88, we observed an inhibition of canonical Wnt signaling due to interactions of TMEM88 with the Wnt pathway factor Dishevelled (DVLS). In contrast, NSCLC cells with cytosol-localized TMEM88 lacked effects on Wnt signaling. Cytosolic interactions of TMEM88 and DVLS increased the expression of phosphorylated, active forms of p38, GSK3β (Thr390), and Snail, thereby reducing the expression of the tight junction-associated proteins ZO-1 and occludin, effects associated with enhanced invasive and metastatic cell characters. Importantly, attenuating the expression of cytosolic TMEM88 reduced metastatic prowess in xenograft models. Overall, our findings show how mislocalization of TMEM88 to the cytosol in NSCLC cells ablates its Wnt pathway regulatory properties, thereby promoting invasion and metastasis by activating the p38-GSK3β-Snail signaling pathway.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3828DOI Listing
November 2015

Pseudomyogenic hemangioendothelioma/epithelioid sarcoma-like hemangioendothelioma of the lower limb: report of a rare case.

Diagn Pathol 2015 Aug 28;10:150. Epub 2015 Aug 28.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, 110001, Shenyang, China.

Pseudomyogenic hemangioendothelioma is an extremely rare soft tissue tumor, also named as epithelioid sarcoma-like hemangioendothelioma, which occurs more frequently in young adult males. It was originally recognized as a variant of epitheloid sarcoma, however it is now concluded as a distinctive, rarely metastasizing endothelial neoplasm. We present a case of pseudomyogenic hemangioendothelioma in the lower limb in a 49-year-old female who has a long course of disease and suffered from twice local recurrences and lymph node affection of the tumor. The mass was subcutaneous and the margins were ill-defined. Morphologically, the tumor cells show diversity, composed of large spindle cells and round cells, both with abundant eocinophilic cytoplasm, mimicking rhybdomyoplasts and epitheloid cells respectively. The tumor cells show diffuse strong expression of Factor VIII, Fli-1, INI-1, vimentin, MDM2, and CDK4, local expression of CD31, AE1/AE3, EMA and P63, and no expression of CD34, S-100, actin-sm, desmin, MyoD1, and HMB45. Based on these information, this case is diagnosed as pseudomyogenic hemangioendothelioma after ruling out the main differential diagnosises including epithelioid sarcoma, malignant peripheral nerve sheath tumor and rhabdomyosarcoma. From this case we suggest that pseudomyogenic hemangioendothelioma may be confused with a variety of soft tissue neoplasm histologically. The clinical feature of the case of a long course of disease with twice local recurrences and final lymph node involvement 10 years after excision of the primary tumor indicates a relative indolent behavior of this tumor.
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http://dx.doi.org/10.1186/s13000-015-0384-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552433PMC
August 2015

Prevalence and genotype distribution of human papillomavirus infection in asymptomatic women in Liaoning province, China.

J Med Virol 2015 Jul 16;87(7):1248-53. Epub 2015 Apr 16.

Department of Gynecology, First Affiliated Hospital of China Medical University, Shenyang, China.

Infection by human papillomavirus (HPV) is a necessary cause of cervical cancer. The purpose of this study was to investigate the prevalence and genotype distribution of HPV infection in Chinese women who were asymptomatic for cervical diseases. Cervical cytology samples were collected from 6479 asymptomatic Chinese women of Liaoning province, and tested for various HPV genotypes using a chip hybridization assay. HPV was found in 10.3% of all the asymptomatic women studied, with the prevalence of high risk HPV (HR HPV) and low risk HPV (LR HPV) being 9.5% and 1.1%, respectively. HPV genotypes 16, 52, and 58 were found the most frequently genotypes in the HR HPV positive women, and were present in 26.2%, 19.4% and 13.8%, respectively. A graph of HR HPV positive infection rates as a function of age is U-shaped, with a peak in women less than 30 years old and a second peak among women older than 50 years. Nearly half of the women infected with either HR HPV or LR HPV presented a normal looking cervix upon visual examination. The current study demonstrates that the epidemiology of HPV infection in asymptomatic Chinese women in Liaoning province is different from that in women from other regions, even from patients with cervical lesions in the same region. These findings could be used to guide the generation and design of an HPV vaccine for this population.
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http://dx.doi.org/10.1002/jmv.24029DOI Listing
July 2015

Epithelioid angiosarcoma at chest wall which needs to be carefully distinguished from malignant mesothelioma: report of a rare case.

Int J Clin Exp Pathol 2014 1;7(12):9056-60. Epub 2014 Dec 1.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University Shenyang 110001, China ; Institute of Pathology and Pathophysiology, China Medical University Shenyang 110001, China.

Angiosarcoma is a malignant soft tissue tumor the cells of which variably recapitulate the morphologic and functional features of normal endothelium. Most lesions are located in the deep muscles of the lower extremities followed by the arm, trunk and head and neck. Herein we present a case of epithelioid angiosarcoma which is a variant of angiosarcoma at chest wall in a 73-year-old female. Morphologically, the tumor cells are arranged predominantly in luminal structures which can be seen in both angiosarcoma and malignant mesothelioma. Most of the tumor cells are large rounded "epithelioid" cells with abundant eosinophilic cytoplasm which can be also seen in both tumors. The epithelioid of cytomorphology and the localization at chest wall of this case may remind of a diagnosis of malignant mesothelioma which should be carefully distinguished from epithelioid angiosarcoma from imaging and morphology. CT scanning of the patient shows a mass at her chest wall, the majority of which is around the rib but not inside the lung which indicates a tumor originates more likely from soft tissues of chest wall but not pleura. Immunohistochemical staining shows that the tumor cells are positive for cytokeratin, CD31, Vimentin and WT1, and negative for CEA, TTF-1, Calretinin, Mesothelial Cell (MC), CD56, CK19, and Hepatocyte. Thus this case is diagnosed as epithelioid angiosarcoma but not malignant mesothelioma. From this case we suggest that carefully reading and understanding of the imaging are a very important clue for appropriate diagnosis. A misdiagnosis may occur on the basis of misunderstanding of tumor localization and a consequent inappropriate immunohistochemical staining programme.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314036PMC
October 2015

Coexpression of IQ-domain GTPase-activating protein 1 (IQGAP1) and Dishevelled (Dvl) is correlated with poor prognosis in non-small cell lung cancer.

PLoS One 2014 1;9(12):e113713. Epub 2014 Dec 1.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Background: IQ-domain GTPase-activating protein 1 (IQGAP1) binds to Dishevelled (Dvl) and functions as a modulator of Dvl nuclear localization in Xenopus embryos. However, the relationship between IQGAP1 and Dvl in tumor tissues is unclear.

Materials And Methods: We used immunohistochemistry to assess the expressions of IQGAP1 and Dvl in a cohort of 111 non-small cell lung cancer (NSCLC) patients. Association of their localization expressions with clinicopathological factors was also analyzed.

Results: The positive rate of IQGAP1 in primary tumors was 48.6% (54/111) for its cytoplamic expression, 9.0% (10/111) for nuclear expression and 31.5% (35/111) for membranous expression; the positive rate of Dvl was 65.8% (73/111) for cytoplamic expression, 9.9% (11/111) for nuclear expression and 10.8% (12/111) for membranous expression. Coexpression rate of IQGAP1 and Dvl was 77.8% (42/54) in the cytoplasm, 80.0% (8/10) in the nucleus and 8.6% (3/35) in the membrane. Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus were significantly correlated (P<0.05), but not in the membrane (P>0.05). The positive expression rates of cyclin D1 and c-myc were significantly higher in the group of IQGAP1 and Dvl coexpression in the nucleus than that in the cytoplasm. Coexpression rate of IQGAP1 and Dvl in the cytoplasm and nucleus was significantly higher in lymph nodal metastases (63.3%, 19/30) than in primary growths (38.3%, 31/81), correlating with poor prognosis. Five-year survival time after resection in the group with their coexpression in the cytoplasm and nucleus was significantly lower than that with no coexpression (44.705±3.355 vs 58.403±2.543 months, p<0.05).

Conclusions: Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus was correlated with the lymph nodal metastase and poor prognosis of NSCLC, and coexpression in nucleus might play a critical role in the activation of canonical Wnt pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113713PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249885PMC
September 2015

Promoter methylation-mediated silencing of β-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis.

PLoS One 2014 14;9(11):e112258. Epub 2014 Nov 14.

Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.

β-Catenin plays dual role in adhesion complex formation and the Wnt signaling pathway. Although β-catenin expression appears to be upregulated and Wnt signaling pathway is activated in the majority of cancers, its expression level seems to be lost in non-small cell lung cancer (NSCLC). We previously reported that the promoter of β-catenin was hypermethylated in two NSCLC cell lines. In the current study, we expanded our analysis for the methylation status of β-catenin promoter region and its protein expression in seven NSCLC cell lines and a series of 143 cases of primary human lung cancer with adjacent non-neoplastic tissues. Quantitative methylation specific PCR (qMSP) analysis showed methylation of β-catenin promoter region in five NSCLC cell lines, with increased β-catenin protein levels upon 5'-Aza-2'-deoxycytidine (5-aza-dC) treatment. The methylation status in SPC (methylated) and A549 (unmethylated) was confirmed by bisulfite sequencing PCR. 5-Aza-dC treatment inhibited invasiveness of SPC but not A549. Immunofluorescence analysis showed membranous β-catenin expression was lost in SPC and could be re-established by 5-aza-dC, while Wnt3a treatment led to nuclear translocation of β-catenin in both SPC and A549. Dual-luciferase assays indicated that 5-aza-dC treatment caused no significant increase in Wnt signaling activity compared with Wnt3a treatment. The effect of demethylation agent in SPC can be reversed by β-catenin depletion but not E-cadherin depletion which indicated that the methylation mediated β-catenin silencing might enhance NSCLC invasion and metastasis in an E-cadherin independent manner. Subsequent immunohistochemistry results further confirmed that β-catenin promoter hypermethylation correlated with loss of immunoreactive protein expression, positive lymph node metastasis, high TNM stage and poor prognosis. The present study implicates β-catenin promoter hypermethylation in the mechanism of epigenetic changes underlying NSCLC metastasis and progression, thus indicating the potential of β-catenin as a novel epigenetic target for the treatment of NSCLC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232381PMC
July 2015

Zbed3 contributes to malignant phenotype of lung cancer via regulating β-catenin and P120-catenin 1.

Mol Carcinog 2015 Jun 27;54 Suppl 1:E138-47. Epub 2014 Sep 27.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.

Our previous studies indicate that abnormal expression of several Wnt signaling molecules including Axin, Dvl and β-catenin are involved in proliferation, invasion and metastasis of lung cancer. Zbed3 was found to inhibit function of Axin-GSK3β complex and thus lead to accumulation of β-catenin in NIH3T3 and HEK293T cells. However its function in malignant tumors is largely unknown. Here we investigate the clinico-pathological significance of Zbed3 expression and its function in non-small cell lung cancer. We use immunohistochemistry and Western blotting to examine Zbed3 expression in non-small cell lung cancer and lung tissues. Transfection of siRNA and plasmid was used to study the function of Zbed3 in lung cancer cells in vitro. We found Zbed3 expression was elevated in cancer tissues compared to normal lung tissues. Increased Zbed3 expression is significantly associated with lymph node metastasis, advanced TNM stages, higher Ki67 status and patients' poor clinical outcome. Higher Zbed3 expression was also found in lung cancer cell lines compared to bronchial epithelial cell line HBE. Downregulation of Zbed3 by siRNA significantly inhibits cancer cell proliferation and invasion in vitro. Downregulation of Zbed3 also significantly inhibits expression of β-catenin, downstream molecules of Wnt signaling and P120ctn-1 in lung cancer cells. These results suggest that Zbed3 may contribute to lung cancer cell invasion through regulating β-catenin and p120ctn-1 and may be a promissing cancer marker in non-small cell lung cancer.
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http://dx.doi.org/10.1002/mc.22216DOI Listing
June 2015

Btbd7 contributes to reduced E-cadherin expression and predicts poor prognosis in non-small cell lung cancer.

BMC Cancer 2014 Sep 24;14:704. Epub 2014 Sep 24.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang 110001, China.

Background: Disorders of cell adhesion are critical steps in cancer progression in which varieties of markers including cadherins are involved in.Btbd7 was found to inhibit E-cadherin expression in MDCK cells and play important roles during branching morphogenesis of embryonic salivary glands and lungs. However its function in malignant tumors is largely unknown. The aim of this study is to investigate the clinicopathological significance and possible function of Btbd7 in non-small cell lung cancer.

Methods: Immunohistochemistry and Western blotting were used to investigate Btbd7 expression in non-small cell lung cancer and lung tissues. The clinicopathological association and the overall survival was analyzed. In vitro experiments were performed using siRNA to investigate the function of Btbd7 in lung cancer cells.

Results: Btbd7 expression was elevated in non-small cell lung cancer tissues compared to normal lung tissues. Increased Btbd7 expression was significantly associated with lymph node metastasis, reduced E-cadherin expression and patients' poor clinical outcome. Downregulation of Btbd7 expression in lung cancer cells by siRNA significantly inhibits cancer cell invasion and effectively restores E-cadherin expression in cancer cell membrane.

Conclusions: Btbd7 contributes to reduced expression of E-cadherin and may be a promising cancer marker in non-small cell lung cancer.
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http://dx.doi.org/10.1186/1471-2407-14-704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189533PMC
September 2014

Armc8 expression was elevated during atypia-to-carcinoma progression and associated with cancer development of breast carcinoma.

Tumour Biol 2014 Nov 14;35(11):11337-43. Epub 2014 Aug 14.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, 110001, Shenyang, China,

Armadillo repeat-containing protein 8 (Armc8) is a key factor to regulate cell membrane adhesion complex through promoting α-catenin degradation. However, its expression and function in human malignant tumors are largely unknown. Here, we present our study investigating Armc8 expression in tumor and non-tumor breast tissues including 45 normal epithelia, 53 lesions of hyperplasia with or without dysplasia, 22 benign tumors, and 92 carcinomas including 28 carcinomas in situ and 64 infiltrating carcinomas using immunohistochemistry (IHC) and Western blotting study. Armc8 expression was detected mainly in the cytoplasm with occasional membrane immunostaining. The positive rate of Armc8 expression in normal breast epithelia (8.9%, four out of 45) was very low. No significant difference was found between Armc8 expression in usual ductal hyperplasia (UDH) (11.1%, two out of 18), benign breast tumors including intraductal papilloma (10.0%, one out of 10) and fibroadenoma (8.3%, one out of 12), and normal breast epithelia (p>0.05). Elevated expression of Armc8 was found in breast epithelia with dysplasia (24.0%, six out of 25) compared to that in normal breast epithelia, UDH, and benign breast tumors (p<0.05). Armc8 expression in breast carcinoma including breast carcinoma in situ (10/28, 35.7%), infiltrating ductal carcinoma (60.7%, 34/56), and infiltrating lobular carcinoma (50.0%, 4/8) was higher than that in normal breast epithelia, UDH, benign breast tumors, and breast epithelia with dysplasia (p<0.05). The highest expression of Armc8 was found in infiltrating breast carcinoma (59.4%, 38/64) compared to all the other breast tissues. Higher Armc8 expression was found to be linked to lymph node metastasis and advanced tumor-node-metastasis (TNM) stages (III+IV) in infiltrating breast carcinoma (p<0.05). We further confirmed Armc8 expression in breast epithelial cell line MCF10A and breast carcinoma cell lines including MCF-7, MDA-MB-231, and ZR751 using Western blotting and immunofluorescent study. These results indicate that the elevated expression of Armc8 may be involved in carcinogenesis including atypia-to-carcinoma progression and cancer development of breast carcinoma.
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http://dx.doi.org/10.1007/s13277-014-2473-0DOI Listing
November 2014

ARMC8α promotes proliferation and invasion of non-small cell lung cancer cells by activating the canonical Wnt signaling pathway.

Tumour Biol 2014 Sep 4;35(9):8903-11. Epub 2014 Jun 4.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

ARMC8 proteins are novel armadillo repeat containing proteins, which are well conserved in eukaryotes and are involved in a variety of processes such as cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. Armadillo repeat proteins include well-known proteins such as β-catenin and p120ctn. Our current knowledge of ARMC8, especially its role in cancer, is limited. In this study, we quantified ARMC8 expression in 112 non-small cell lung cancer (NSCLC) tissues and adjacent non-cancerous tissues, and seven lung cancer cell lines using immunohistochemistry staining and Western blotting. ARMC8 level was significantly higher in NSCLC tissues than in the adjacent normal tissues (67.9 % versus 5.4 %, p < 0.05) and was significantly associated with TNM stage (p = 0.022), lymph node metastasis (p = 0.001), and poor prognosis (p < 0.001) in NSCLC patients. Cox regression analysis demonstrated that ARMC8 was an independent prognostic factor for NSCLC. Consistent with this, ARMC8α downregulation by siRNA knockdown inhibited growth, colony formation, and invasion in A549 lung cancer cells, while ARMC8α overexpression promoted growth, colony formation, and invasion in H1299 lung cancer cells. In addition, ARMC8α knockdown downregulated canonical Wnt-signaling pathway activity and cyclin D1 and matrix metalloproteinase (MMP)-7 expression. Consistent with this, ARMC8α overexpression upregulated canonical Wnt-signaling pathway activity and cyclin D1 and MMP-7 expression. These results indicate that ARMC8α upregulates cyclin D1 and MMP7 expression by activating the canonical Wnt-signaling pathway and thereby promoting lung cancer cell proliferation and invasion. Therefore, ARMC8 might serve as a novel therapeutic target in NSCLC.
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http://dx.doi.org/10.1007/s13277-014-2162-zDOI Listing
September 2014

ASAP3 expression in non-small cell lung cancer: association with cancer development and patients' clinical outcome.

Tumour Biol 2014 Feb;35(2):1489-94

ASAP3 belongs to Arf-specific GTPase-activating proteins which regulate Arfs by stimulating their intrinsic GTP hydrolysis. ASAP3 expression and the clinical significance in malignant tumors are largely unknown. In this study, we examined ASAP3 expression in non-small cell lung cancer (NSCLC) to find out its clinicopathological significance. Immunohistochemistry shows elevated expression of ASAP3 in cancer tissues (54.8 % (57/104)) compared to normal lung tissues (18.0 % (9/50)) (p < 0.05). Increased ASAP3 expression was associated with poor differentiation, lymph node metastasis, and advanced TNM stages in NSCLC (p < 0.05). Survival analysis reveals that ASAP3 expression contributes to patients' poor clinical outcome (p < 0.05). We also examined ASAP3 expression in several lung cancer cell lines using Western blotting. We downregulated ASAP3 expression in LTE cell which has a relative high level of ASAP3 expression using siRNA and found that reduced ASAP3 leads to significant inhibition of cancer cell invasion (p < 0.05). These data indicate that ASAP3 is elevated in NSCLC and may contribute to cancer development and patients' poor clinical outcome, which is possibly due to its critical roles in regulating cancer invasion.
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http://dx.doi.org/10.1007/s13277-013-1205-1DOI Listing
February 2014

Clinical significance and biological roles of SPAG9 overexpression in non-small cell lung cancer.

Lung Cancer 2013 Aug 24;81(2):266-72. Epub 2013 May 24.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.

To investigate the expression pattern of SPAG9 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We checked a panel of 120 NSCLC tissues and 20 corresponding normal lung tissues by immumohistochemistry. We observed negative staining in the normal bronchial epithelia and positive staining of SPAG9 in 63 out of 120 (52.5%) NSCLC samples. Overexpression of SPAG9 correlated with poor tumor differentiation (p = 0.002), advanced p-TNM stage (p = 0.0001), nodal metastasis (p = 0.0061) and poor overall survival (p = 0.0001). We silenced SPAG9 gene in A549 and H1299 cells by specific siRNA and found that silencing SPAG9 expression inhibited cell growth and invasion. In addition, the protein and mRNA levels of MMP9 were also down-regulated in SPAG9 knocked down cells. Further research demonstrated SPAG9 depletion could inhibit the activity of p-JNK. In conclusion, SPAG9 might act as an important promoter in lung cancer progression and invasion via MMP9 regulation and JNK activation.
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http://dx.doi.org/10.1016/j.lungcan.2013.04.021DOI Listing
August 2013

DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1.

Int J Mol Med 2013 Apr 19;31(4):855-60. Epub 2013 Feb 19.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, PR China.

Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is a basic helix-loop-helix transcriptional regulator, reportedly involved in cell growth, differentiation, apoptosis and tumorigenesis. In breast cancer, DEC1 expression correlates with increased malignant potential and invasiveness. Nevertheless, the detailed mechanisms by which DEC1 modulates breast cancer progression are still unclear. Claudin-1, an important tight junction protein, functions as a tumor invasion suppressor. In the present study, the relationship between DEC1 and claudin-1 in 147 cases of invasive breast ductal carcinomas was examined by immunohistochemistry. Based on the data, DEC1 expression was elevated in invasive breast ductal carcinomas and DEC1 levels were positively correlated with tumor grade (P=0.023). Moreover, DEC1 expression was negatively correlated with the claudin-1 level (correlation coefficient =-0.245, P=0.003). We further identified that, in MCF-7 and MDA-MB-231 breast cancer cell lines, DEC1 knockdown led to the enhanced expression of claudin-1 at both the mRNA and protein levels, and reduced cell invasive capacity. Collectively, our data suggest that overexpression of DEC1 may promote the invasiveness of breast cancer through downregulation of claudin-1.
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http://dx.doi.org/10.3892/ijmm.2013.1279DOI Listing
April 2013

Low-grade cribriform cystadenocarcinoma of salivary glands: report of two cases and review of the literature.

Diagn Pathol 2013 Feb 18;8:28. Epub 2013 Feb 18.

Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Unlabelled: Low-grade cribriform cystadenocarcinoma (LGCCC) is a recently described rare tumor of salivary gland which exhibits clinically indolent behavior. This tumor predominantly consists of intraductal components and frequently exhibits papillary-cystic or cribriform proliferation pattern. Considering the histological features of LGCCC, it should be distinguished with papillocystic variant of acinic cell carcinoma, conventional salivary duct carcinoma, cystadenocarcinoma, polymorphous low-grade adenocarcinoma, carcinoma ex pleomorphic adenoma and mammary analogue secretory carcinoma. Herein, we presented two cases of LGCCC. One arose in the left parotid region in a 48-year-old male, and the other one arose in the right parotid gland in a 59-year-old female. For both cases, immunohistochemically, the luminal tumor cells showed diffuse expression of CK and S100; p63 and smooth muscle actin displayed a continuous rim of myoepithelial cells around all tumor islets; no myoepithelial cells were admixed with the luminal cells. Both patients were alive with no tumor recurrence or metastasis at follow-up.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2593621568999135.
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http://dx.doi.org/10.1186/1746-1596-8-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598350PMC
February 2013