Publications by authors named "Enhua Wang"

212 Publications

Noninvasive papillary urothelial carcinoma with pathological features in between low and high grades: A case report.

Medicine (Baltimore) 2021 Apr;100(17):e25693

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

Rationale: Urinary bladder urothelial carcinoma is the most common malignant tumor in the urinary system, and noninvasive papillary urothelial carcinoma (NIPUC) comprises most bladder malignancies. NIPUC grading is important for therapeutic and clinical protocol selection. Here, we report a case of NIPUC with pathological features in between low (LG-NIPUC) and high (HG-NIPUC) grades NIPUC.

Patient Concerns: A 72-year-old male, presenting with a 20-year history of hypertension and 5 months of hematuria.

Diagnoses: Computed tomography examination revealed a tumor in the urinary bladder neck. Microscopic investigation revealed that most tumor tissue samples had a branching papillary architecture, with well-developed fibrous-vascular cores. Tumor cells were slightly crowded, with somewhat altered cell polarity and cell adhesion. Immunohistochemistry showed positive Ki67 staining, mostly in the basal layer, while p53 staining was rarely positive. These samples were diagnosed as LG-NIPUC. However, a few tumor tissue samples presented mildly fused papillary architectures without cell polarity or adhesion. Most nuclei stained intensely and were pleomorphic. All epithelial tissue layers were ki67 positive, and the p53 positive rate was higher than that in the LG samples. Therefore, these were classified as HG-NIPUC.

Interventions: The tumor was completely resected during lithotomy postural surgery.

Outcomes: The patient is alive with a good recovery during 3 months after the surgery.

Lessons: We diagnosed this patient as having LG-NIPUC with local HG-NIPUC components. HG- and LG-HIPUC have different outcomes. This case is a new challenge for the pathological grading of NIPUC. An intermediate HIPUC grade might need to be added to the original NIPUC grading system.
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http://dx.doi.org/10.1097/MD.0000000000025693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084004PMC
April 2021

Clinicopathologic features and treatment of thymic lymphoepithelioma-like carcinoma: two case reports and literature review.

Am J Transl Res 2021 15;13(3):1896-1903. Epub 2021 Mar 15.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University No. 155 Nanjing North Street, Heping District, Shenyang 110001, Liaoning, China.

Lymphoepithelioma-like carcinoma (LELC) is rare in the thymus, and easily misdiagnosed. To improve its clinicopathologic knowledge, we describe two cases of thymic LELC, and investigate their microscopic and immunohistochemical features, treatment, and follow-up with a review of previously published cases. Two patients in the First Affiliated Hospital of China Medical University underwent complete surgical resection for thymic LELC. They were treated with chemotherapy or radiotherapy after operation. Histologically, tumor cells exhibited nest patterns or showed stripe-shaped infiltration in fibrous tissue containing lymphocytes. Tumor was diffusely positive for pan-cytokeratin (CK), CK19, cluster of differentiation 5 (CD5), CD117, epithelial membrane antigen (EMA), and p63, and negative for TdT. Recent follow-up showed that the two patients were alive with no signs of recurrence. We report two cases of thymic LELC with a review of previously published cases to summarize knowledge of their clinicopathological characteristics, which is necessary for accurate diagnosis and clinical treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014405PMC
March 2021

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

PWP1 Promotes the Malignant Phenotypes of Lung Cancer Cells by Interacting with DVL2 and Merlin.

Onco Targets Ther 2020 8;13:10025-10037. Epub 2020 Oct 8.

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

Purpose: The significance of periodic tryptophan protein 1 (PWP1) expression in human cancer and its molecular mechanism of action have not been reported so far.

Materials And Methods: Immunohistochemistry was performed to analyze the expression of PWP1 in non-small cell lung cancer (NSCLC) tissues and statistical analysis was applied to analyze the relationship between PWP1 expression and the clinicopathological factors. The effects of PWP1 on NSCLC proliferation and invasion were determined by colony formation, transwell and MTT assays. Western blot analysis (WB), dual-luciferase reporter gene assays and immunofluorescence staining were performed to demonstrate whether PWP1 stimulates Wnt pathway and inhibits Hippo pathway. Co-immunoprecipitation (Co-ip) assays were used to confirm the potential role of PWP1 in Wnt and Hippo signaling pathways.

Results: PWP1 expression in NSCLC was higher than that in normal bronchial epithelium and normal submucosal glands. In addition, PWP1 expression had a positive correlation with poor differentiation, high pathological tumor-node-metastasis (TNM) stage, and lymph node metastasis. Kaplan-Meier database demonstrated that the overall survival time of patients with high PWP1 expression was significantly shorter than that of patients with low PWP1 expression. Mechanistically, we found that PWP1 could interact with DVL2 to upregulate β-catenin (thereby activating the Wnt pathway), whereas PWP1 could interact with Merlin (NF2) to downregulate p-MST1 (thereby inhibiting the Hippo signaling pathway). The effects of PWP1 on promoting the Wnt pathway or inhibiting the Hippo pathway were offset in DVL2- or Merlin-knockdown cells transiently overexpressing PWP1.

Conclusion: PWP1 expression in NSCLC was correlated with poor prognosis. PWP1 enhanced the activity of the Wnt pathway by interacting with DVL2, whereas PWP1 inhibited the activity of the Hippo pathway by interacting with Merlin. Together, these two effects promoted the detrimental biological behaviors of NSCLC cells.
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http://dx.doi.org/10.2147/OTT.S263815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553635PMC
October 2020

WW and C2 domain-containing protein-3 promoted EBSS-induced apoptosis through inhibiting autophagy in non-small cell lung cancer cells.

J Thorac Dis 2020 Aug;12(8):4205-4215

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

Background: WW and C2 domain-containing protein-3 (WWC3) was identified in our previous studies as a tumor suppressor gene, which inhibits the proliferation and invasiveness of lung cancer cells. However, the relationship between WWC3 and autophagy and apoptosis in lung cancer cells is unclear. In this study, we aimed to investigate the potential role of WWC3 in starvation-induced autophagy and apoptosis in non-small cell lung carcinoma (NSCLC) cells.

Methods: The immunoblotting assay and quantitative real-time polymerase chain reaction (RT-qPCR) were used for observing the change of WWC3 protein and mRNA level under starvation condition. The immunoblotting assay and immunofluorescence assay were performed to detect the impact of WWC3 expression on autophagy process induced by Earle's balanced salt solution (EBSS) in lung cancer cells; APC/propidium iodide (PI) apoptosis assay, caspase-3/7 activity assay and MTT assay were used for the apoptosis and proliferation detection of lung cancer cells.

Results: After starvation had been induced with EBSS, WWC3 expression was significantly decreased in the NSCLC cells. Ectopic WWC3 expression weakened the autophagy process in a Beclin1-independent manner and promoted non-small cell lung cancer cell apoptosis via EBSS starvation. Moreover, the inhibition of WWC3 gene knockout was weakened by 3-methyladenine (3-MA), an autophagy inhibitor.

Conclusions: These results indicate that WWC3 promotes apoptosis and death of starved lung cancer cells, at least partly through autophagy.
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http://dx.doi.org/10.21037/jtd-20-966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475589PMC
August 2020

Corrigendum to "A novel long non-coding RNA LINC00355 promotes proliferation of lung adenocarcinoma cells by down-regulating miR-195 and up-regulating the expression of CCNE1" [Cell Signal. 2020 Feb;66:109462. doi: 10.1016/j.cellsig.2019.109462].

Cell Signal 2020 Sep 21;73:109715. Epub 2020 Jul 21.

Department of Pathology, College of Basic Medical Science and First Affiliated Hospital, China Medical University, Shenyang 110122, PR China.

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http://dx.doi.org/10.1016/j.cellsig.2020.109715DOI Listing
September 2020

BHLHE41 suppresses MCF-7 cell invasion via MAPK/JNK pathway.

J Cell Mol Med 2020 04 19;24(7):4001-4010. Epub 2020 Feb 19.

Department of Pathology, The First Affiliated Hospital, China Medical University, Shenyang, China.

Deregulation of the basic helix-loop-helix family member e41 (BHLHE41) has been characterized as a marker of progression of several cancers. In this study, we aimed to explore the mechanism by which BHLHE41 regulates the invasion of breast cancer cells. BHLHE41 suppresses, whereas the silencing of BHLHE41 promotes tumour invasion of both MCF-7 and MDA-MB-231 cells. Meanwhile, BHLHE41 down-regulated the transcription and translation of SNAI1, SNAI2, VIM and CDH2, and up-regulated those of CLDN1, CLDN4 and CDH1. Reporter assay indicated that silencing of BHLHE41 dramatically activated the MAPK/JNK signalling pathway in MCF-7 cell line and the hypoxia signalling pathway in MDA-MB-231 cell line. Furthermore, silencing of BHLHE41 activated the MAPK/JNK signalling pathway by up-regulating phosphorylated JNK and failed to affect the expression of HIF-1 alpha in MCF-7 cells. After blocking the MAPK/JNK signalling pathway by specific inhibitor SP600125, silencing of BHLHE41 failed to promote tumour cell invasion. These results suggest that BHLHE41 facilitates MCF-7 cell invasion mainly via the activation of MAPK/JNK signalling pathway. In conclusion, although BHLHE41 suppresses tumour invasion in MCF-7 and MDA-MB-231 cell lines, the specific regulatory mechanisms may be different.
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http://dx.doi.org/10.1111/jcmm.15033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171311PMC
April 2020

A novel long non-coding RNA LINC00355 promotes proliferation of lung adenocarcinoma cells by down-regulating miR-195 and up-regulating the expression of CCNE1.

Cell Signal 2020 02 2;66:109462. Epub 2019 Nov 2.

Department of Pathology, College of Basic Medical Science and First Affiliated Hospital, China Medical University, Shenyang, 110122, PR China. Electronic address:

Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer affecting people all over the globe. Recent studies have indicated that long non-coding RNAs (lncRNAs) possess the ability to regulate gene expression. Initially, we uncovered increased LINC00355 expressions in lung adenocarcinoma tissues and cells. Functionally, our findings demonstrated that LINC00355 silencing suppressed the proliferation in vitro and in vivo. In addition, we found that LINC00355 negatively regulated miR-195 in lung adenocarcinoma cells. Simultaneously, silencing LINC00355 by shRNA resulted in suppressed proliferation, colony formation and promoted cell cycle arrest and apoptosis via miR-195. Moreover, silencing LINC00355 by shRNA inhibited the cyclin E1 (CCNE1) gene expression via miR-195 in lung adenocarcinoma cells. Collectively, this study demonstrates the novel lncRNA LINC00355 in regulatory network of CCNE1 via miR-195 in lung adenocarcinoma, highlighting LINC00355 as a new target for the treatment of lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.cellsig.2019.109462DOI Listing
February 2020

Glucose Transporter 1 Promotes the Malignant Phenotype of Non-Small Cell Lung Cancer through Integrin β1/Src/FAK Signaling.

J Cancer 2019 27;10(20):4989-4997. Epub 2019 Aug 27.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, China.

: Glucose transporter 1 (GLUT1) is the main factor of Warburg effect, which is associated with poor prognosis in many tumors. However, the underlying molecular mechanism of GLUT1 in the progression of non-small cell lung cancer (NSCLC) is unclear. : We used quantitative real-time PCR to detect GLUT1 mRNA expression in bronchial brushing samples and performed Western Blot and biological behavior testing to check the effect of GLUT1 on NSCLC cell proliferation, migration, invasion and apoptosis. : We found that the C(t) normalized value of GLUT1 in malignant bronchial brushing samples was significantly higher than that in benign samples (<0.05). GLUT1 significantly increased the expressions of cyclin A, cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), CDK4, CDK6 and matrix metalloproteinase 2 (MMP2), but decreased the expressions of p53 and p130 in NSCLC cells. The biological behavior testing indicated that GLUT1 enhanced NSCLC cell proliferation, invasion and migration but inhibited cell apoptosis. In addition, GLUT1 upregulated the expression of integrin β1 and promoted the phosphorylation of focal adhesion kinase (FAK, phosphorylation at Tyr576/577) and Src (Src phosphorylation at Tyr530). siRNA knock down of integrin β1 expression suppressed GLUT1 induced NSCLC cell biological behavior, as well as the phosphorylation of FAK and Src. : Taken together, our data confirms that GLUT1 promotes the malignant phenotype of NSCLC through integrin β1/Src/FAK signaling, which provides a new therapeutic target for the treatment and research of lung cancer.
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http://dx.doi.org/10.7150/jca.30772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775508PMC
August 2019

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

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

RASSF10 suppresses lung cancer proliferation and invasion by decreasing the level of phosphorylated LRP6.

Mol Carcinog 2019 07 4;58(7):1168-1180. Epub 2019 Mar 4.

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

Ras-association domain family (RASSF) proteins exert distinct cellular functions. The expression of RASSF10 in non-small cell lung cancer and its underlying mechanism have not been reported. Herein, we explored the roles of RASSF10 in lung cancer cells and potential molecular mechanisms. We found low RASSF10 expression in lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients. Furthermore, RASSF10 overexpression inhibited the proliferation and invasion of lung cancer cells, which was the result of Wnt signaling suppression. However, we found that RASSF10 had no influence on Hippo signaling, while RASSF10 bound to LRP6 via the coiled-coil domains and reduced p-LRP6 level, eventually prohibiting β-catenin nuclear translocation. However, deleting the coiled-coil domains ablated this function. These findings expound the interaction between RASSF10 and LRP6 and uncover a potential link between N-terminal RASSFs and the Wnt pathway.
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http://dx.doi.org/10.1002/mc.23000DOI Listing
July 2019

Ajuba overexpression regulates mitochondrial potential and glucose uptake through YAP/Bcl-xL/GLUT1 in human gastric cancer.

Gene 2019 Apr 25;693:16-24. Epub 2019 Jan 25.

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

Ajuba dysregulation has been reported in several human cancers. However, its expression patterns and biological roles in human gastric cancers have not yet been characterized. In the current study, we found that Ajuba protein was increased in gastric cancer tissues and in cell lines. High Ajuba expression positively correlated with the tumor-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis. The Cancer Genome Atlas (TCGA) and Oncomine microarray data mining also suggested that Ajuba mRNA upregulation in gastric cancer tissues. We used SGC-7901 and NCI-N87 cell lines for Ajuba overexpression and siRNA knockdown respectively. MTT and colony formation assays indicated that Ajuba overexpression increased proliferation rate and colony formation ability while Ajuba siRNA inhibited proliferation rate and colony formation ability. AnnexinV and JC1 staining showed that Ajuba downregulated cisplatin induced apoptosis while it upregulated mitochondrial membrane potential. Ajuba overexpression also inhibited caspase-3 and PARP cleavage, while Ajuba depletion showed the opposite effects. Notably, Ajuba enhanced glucose metabolism by upregulating glucose uptake, glucose consumption, lactate production and ATP production. We further revealed that Ajuba positively regulated cyclin D1, Bcl-xL and GLUT1 at both mRNA and protein levels. Analysis of TCGA dataset revealed that there were positive correlations between Ajuba and cyclin D1, Bcl-xL, GLUT1 at the mRNA levels. Further investigation demonstrated that Ajuba overexpression inhibited Hippo signaling by upregulating YAP protein expression. Depletion of YAP by siRNA abolished the effect of Ajuba on cyclin D1, Bcl-xL and GLUT1. Together, our study showed that Ajuba was overexpressed in human gastric cancers, where it increased cell growth and chemoresistance. Our data also identified novel roles of Ajuba in gastric cancer progression involving regulating glucose uptake and mitochondrial function through the YAP-GLUT1/Bcl-xL axis, making it a potential therapeutic target.
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http://dx.doi.org/10.1016/j.gene.2019.01.018DOI Listing
April 2019

ZNF326 promotes proliferation of non-small cell lung cancer cells by regulating ERCC1 expression.

Lab Invest 2019 02 6;99(2):169-179. Epub 2018 Nov 6.

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

The roles and downstream target genes of the transcription factor ZNF326 in malignant tumors are unclear. Out of 146 lung cancer tissue samples, we found that high expression of ZNF326 in 82 samples was closely related to low differentiation and a high pTNM stage of non-small cell lung cancer (NSCLC) cells. In vitro and in vivo analyses showed that ZNF326 significantly promoted cell cycle progression, colony formation, and proliferation as well as the growth of NSCLC transplanted tumors. Chromatin immunoprecipitation sequencing, dual-luciferase assay, and electrophoretic mobility shift assay confirmed that the C2H2 structure of ZNF326 binds to the -833 to -875 bp region of the ERCC1 promoter to initiate transcriptional activity. This binding promoted CyclinB1 synthesis and cell cycle progression. These results show that the ZNF326 transcription factor is highly expressed in lung cancer and promotes the proliferation of NSCLC cells by regulating the expression of ERCC1.
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http://dx.doi.org/10.1038/s41374-018-0148-yDOI Listing
February 2019

Alveolar architectures preserved in cancer tissues may be potential pitfalls for diagnosis and histological subtyping of lung cancer: Three case reports.

Medicine (Baltimore) 2018 Sep;97(39):e12613

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

Rationale: Lung cancer is a leading cause of cancer-related deaths globally. Appropriate histopathological diagnosis and subtyping form the basis and are critical for clinical therapies.

Patient Concerns: Here, we report about 3 patients who had a nodule in the lung. Cancer cells grow in the alveolar cavity in many lung carcinomas. In all our 3 cases preserved alveolar architectures were found in tumor tissues which may lead to diagnostic pitfalls.

Diagnoses: Three patients had tumors that were diagnosed as nonsmall cell lung cancers, including large-cell carcinoma, peripheral squamous cell carcinoma, and large-cell neuroendocrine carcinoma, all of which contained structures of preserved alveolar cells that could be mistaken as malignant glandular components. The preserved alveolar cells formed acinar or duct-like structures enwrapped in the lung cancer tissues or surrounded the nests of cancer cells. Proliferative alveolar cells adjacent to cancer tissues were observed, and papillary structures and marked atypia, both of which may be mistaken as part of adenocarcinoma or carcinoma with glandular differentiation, were also observed.

Interventions: All patients underwent surgery and postoperative chemotherapy.

Outcomes: The patients had no recurrence at 5-, 8-, or 10-month follow-up after the last surgery.

Lessons: Preserved alveolar cells with different architectures may be observed in various lung cancer tissues and may be mistaken as adenocarcinoma or carcinoma with glandular differentiation. Distinct morphological and immunohistochemical features may help distinguish preserved alveolar cells from tumor components.
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http://dx.doi.org/10.1097/MD.0000000000012613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181608PMC
September 2018

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

Effects of RSF-1 on proliferation and apoptosis of breast cancer cells.

Oncol Lett 2018 Oct 18;16(4):4279-4284. Epub 2018 Jul 18.

Staff Room of Pathology, China Medical University, College of Basic Medical Science, Shenyang, Liaoning 110001, P.R. China.

Effect of interference with chromatin remodeling and spacing factor-1 (RSF-1) on proliferation and apoptosis of breast cancer cells was investigated. MCF-7 and SKBR-3 cells were cultured and were divided into 3 groups: control group, negative siRNA control group (NC) and RSF-1 siRNA group. Western blot analysis was used to detect the expression of RSF protein after interference. Cell Counting Kit-8 (CCK-8) method was used to detect the effect of RSF-1 siRNA on cell proliferation. Plate cloning assay was used to detect the effect of RSF-1 siRNA on cell clone formation ability. Annexin V/PI double staining method was used to detect the effect of RSF-1 siRNA on cell apoptosis. Effect of RSF-1 siRNA on nuclear factor-κB (NF-κB) and its downstream signaling pathway were detected by western blot analysis. Western blot analysis showed that RSF-1 siRNA significantly downregulated the expression of RSF-1 protein in MCF-7 and SKBR-3 cells at 72 h after transfection (P<0.01). Cell proliferation assay showed that RSF-1 siRNA significantly reduced the proliferation ability and clone formation ability of MCF-7 and SKBR-3 cells compared with the control group (P<0.01). Annexin V/PI double staining assay results showed that compared with the control group, RSF-1 siRNA significantly increased the apoptosis rate of MCF-7 and SKBR-3 cells (P<0.01). Helenalin and Rsf-1 siRNA significantly reduced the expression levels of p-p65, Bcl-2, and XIAP proteins (P<0.01). Interfering with the expression of RSF-1, gene can effectively inhibit the proliferation of MCF-7 and SKBR-3 cells and promote their apoptosis. RSF-1 can be used as a potential new therapeutic target for the treatment of breast cancer.
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http://dx.doi.org/10.3892/ol.2018.9172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126160PMC
October 2018

TMEM17 promotes malignant progression of breast cancer via AKT/GSK3β signaling.

Cancer Manag Res 2018 2;10:2419-2428. Epub 2018 Aug 2.

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

Purpose: Current knowledge of TMEM17, a recently identified protein of the transmembrane (TMEM) family, is limited, especially with respect to its expression and biological functions in malignant tumors. This study analyzed TMEM17 expression in invasive breast cancer tissue and breast cell lines and its relevance to clinicopathological factors, and investigated the mechanisms underlying the biological effects of TMEM17 on breast cancer cells.

Patients And Methods: TMEM17 protein expression was determined in 20 freshly harvested specimens (tumor and paired normal tissues) by Western blotting. Immunohistochemical analysis was performed to determine the expression and subcellular localization of TMEM17 in samples from 167 patients (mean age, 49 years) diagnosed with invasive ductal carcinoma (38 with triple-negative breast cancer; 129 with non-triple-negative breast cancer) who underwent complete resection in the First Affiliated Hospital of China Medical University between 2011 and 2013. Furthermore, TMEM17 was knocked down by small interfering RNAs in breast cancer cell lines.

Results: TMEM17 was found to be significantly upregulated in breast cancer tissues compared to the corresponding normal breast tissues by Western blotting (=0.015). Immunohistochemical analysis revealed that TMEM was significantly upregulated in invasive breast cancer cells compared to adjacent normal breast duct glandular epithelial cells (10.78% vs 76.05%, <0.001), and its expression was closely related to the patient's T-stage (=0.022), advanced TNM stages (=0.007), and lymph node metastasis (=0.012). After TMEM17 knockdown or overexpression in breast cancer cell lines, TMEM17 upregulated p-AKT, p-GSK3β, active β-catenin, and Snail, and downstream target proteins c-myc and cyclin D1, and downregulated E-cadherin, resulting in increased cancer cell proliferation, invasion, and migration. These effects were reversed by the AKT inhibitor LY294002.

Conclusion: Our results indicate that TMEM17 is upregulated in breast cancer tissues and can promote malignant progression of breast cancer cells by activating the AKT/GSK3β signaling pathway.
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http://dx.doi.org/10.2147/CMAR.S168723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080873PMC
August 2018

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

E3 ubiquitin ligase tripartite motif-containing 71 promotes the proliferation of non-small cell lung cancer through the inhibitor of kappaB-α/nuclear factor kappaB pathway.

Oncotarget 2018 Feb 7;9(13):10880-10890. Epub 2017 Jul 7.

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

Tripartite motif-containing (TRIM) 71 belongs to the TRIM protein family. Many studies have shown that TRIM71 plays conserved roles in stem cell proliferation, differentiation, and embryonic development; however, the relationship between TRIM71 and tumorigenesis is not clear. In this study, we demonstrate that TRIM71 expression in non-small cell lung cancer (NSCLC) is associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis. We found that TRIM71 was highly expressed in NSCLC cell lines compared with that in human normal bronchial epithelial cells. Moreover, by altering the expression of TRIM71 in selected cell lines, we found that TRIM71 promoted the proliferation of NSCLC cells through activation of the inhibitor of kappaB/nuclear factor kappaB pathway. These results suggested that TRIM71 plays a role in promoting the development of NSCLC.
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http://dx.doi.org/10.18632/oncotarget.19075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834285PMC
February 2018

Remodeling and spacing factor 1 overexpression is associated with poor prognosis in renal cell carcinoma.

Oncol Lett 2018 Mar 15;15(3):3852-3857. Epub 2018 Jan 15.

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

The present study aimed to assess the expression and prognostic significance of remodeling and spacing factor 1 (RSF1; HBXAP) in renal cell carcinoma (RCC). RSF1 expression was analyzed using immunohistochemistry on tissue samples from a consecutive series of 137 patients with RCC who underwent tumor resection between November 2000 and March 2004. The associations between RSF1 expression, clinicopathological factors and patient survival were investigated. Immunohistochemistry revealed that RSF1 was highly expressed in 43.1% (59/137) of the RCC samples. RSF1 expression levels were associated with the T stage of the Tumor-Node-Metastasis grading system. Kaplan-Meier survival analysis indicated that high RSF1 expression in RCC was significantly associated with a poor prognosis. Multivariate analysis revealed that RSF1 expression is an independent prognostic parameter for the duration of overall survival of patients with RCC. The results demonstrated that a high expression level of RSF1 in RCC is associated with advanced tumor stages and a poor prognosis. To the best of our knowledge, the present study provides novel evidence of the biological significance of RSF1 expression in RCC.
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http://dx.doi.org/10.3892/ol.2018.7797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796381PMC
March 2018

ARHGEF39 promotes tumor progression via activation of Rac1/P38 MAPK/ATF2 signaling and predicts poor prognosis in non-small cell lung cancer patients.

Lab Invest 2018 05 30;98(5):670-681. Epub 2018 Jan 30.

Department of Pathology, The College of Basic Medicine Science and The First Affiliated Hospital of China Medical University, Shenyang, China.

Rho guanine nucleotide exchange factor 39 (ARHGEF39), also called C9orf100, is a new member of the Dbl-family of guanine nucleotide exchange factors. Although ARHGEF39 has been proven to regulate tumor progression in hepatocellular carcinoma, the downstream signaling pathway of ARHGEF39 and its clinical associations in non-small cell lung cancer (NSCLC) are currently unknown. In the present study, using MTT, colony formation, flow cytometry, mice xenografts, wound healing, and transwell assays, we showed that ARHGEF39 promoted tumor proliferation, migration, and invasion. Furthermore, ARHGEF39 promoted the expression of Cyclin A2, Cyclin D1, and MMP2 by activating Rac1, leading to increased phosphorylation of P38 and ATF2. Treatment with a P38 inhibitor counteracted the effect of ARHGEF39 overexpression on the increase in Cyclin A2, Cyclin D1, and MMP2 expression. Moreover, the elevated levels of p-P38 and p-ATF2 caused by ARHGEF39 overexpression could be inhibited by expression of a dominant negative Rac1 mutant (T17N). In addition, the inhibition of the expression of p-P38 and p-ATF2 by ARHGEF39 RNAi could be restored by the expression of a constitutively active Rac1 mutant (Q61L). A similar impact on cell growth and invasion was observed after ARHGEF39 overexpression combined with the P38 inhibitor, Rac1 T17N, or Rac1 Q61L. Using immunohistochemistry, ARHGEF39 expression was observed to correlate positively with larger tumor size in clinical samples from 109 cases of NSCLC (P = 0.008). The Kaplan-Meier test revealed that ARHGEF39 expression significantly affected the overall survival of patients with NSCLC (52.55 ± 6.40 months vs. 64.30 ± 5.40 months, P = 0.017). In conclusion, we identified that ARHGEF39 promotes tumor growth and invasion by activating the Rac1-P38-ATF2 signaling pathway, as well as increasing the expression of Cyclin A2, Cyclin D1, and MMP2 in NSCLC cells. ARHGEF39 may be a useful marker to predict poor prognosis of patients with NSCLC.
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http://dx.doi.org/10.1038/s41374-018-0022-yDOI Listing
May 2018

Update on research and application of problem-based learning in medical science education.

Biochem Mol Biol Educ 2018 03 29;46(2):186-194. Epub 2017 Dec 29.

Department of Pathology, College of Basic Medical Sciences of China Medical University, Shenyang 110122, China.

Problem-based learning (PBL) is a unique form of pedagogy dedicated to developing students' self-learning and clinical practice skills. After several decades of development, although applications vary, PBL has been recognized all over the world and implemented by many medical schools. This review summarizes and updates the application and study of PBL in medical education through the literature published between 1993 and early 2017. It focuses on understanding real medical PBL courses and ways to improve PBL to achieve better learning outcomes. PBL aims to develop lifelong skills to solve practical problems rather than limiting learning to theoretical knowledge. To achieve this goal, strict and reasonable procedures need to be designed and implemented. Rigorous monitoring and timely feedback and evaluation are indispensable to constant improvements and perfecting of the process. © 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):186-194, 2018.
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http://dx.doi.org/10.1002/bmb.21105DOI Listing
March 2018

Oligothiophene-based colorimetric and ratiometric fluorescence dual-channel cyanide chemosensor: Sensing ability, TD-DFT calculations and its application as an efficient solid state sensor.

Spectrochim Acta A Mol Biomol Spectrosc 2018 Mar 13;193:289-296. Epub 2017 Dec 13.

Shandong Provincial Key Laboratory of Fine Chemicals, School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan 250353, People's Republic of China. Electronic address:

An oligothiophene-based colorimetric and ratiometric fluorescence dual-channel cyanide chemosensor 3 T-2CN was reported. Sensor 3 T-2CN showed both naked-eye recognition and ratiometric fluorescence response for CN with an excellent selectivity and high sensitivity. The sensing mechanism based on the nucleophilic attack of CN on the vinyl CC bond has been successfully confirmed by the optical measurements, H NMR titration, FT-IR spectra as well as the DFT/TD-DFT calculations. Moreover, the detection limit was calculated to be 0.19μM, which is much lower than the maximum permission concentration in drinking water (1.9μM). Importantly, test strips (filter paper and TLC plates) containing 3 T-2CN were fabricated, which could act as a practical and efficient solid state optical sensor for CN in field measurements.
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http://dx.doi.org/10.1016/j.saa.2017.12.039DOI Listing
March 2018

Dact3 inhibits the malignant phenotype of non-small cell lung cancer through downregulation of c-Myb.

Int J Clin Exp Pathol 2017 1;10(12):11580-11587. Epub 2017 Dec 1.

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

Dact3 is a negative regulator of Wnt/β-catenin signaling. c-Myb promotes tumor cell invasion through Wnt/β-catenin pathway. However, the detailed mechanism by which Dact3 and c-Myb modulate the progression of non-small cell lung cancer (NSCLC) remains unclear. In this study, the expressions of Dact3 and c-Myb in 254 surgically resected NSCLC samples were detected by immunohistochemistry. We transfected Dact3 cDNA to A549 and H157 cells or siRNA-Dact3 to SPC cells and examined above effects on the activity of Wnt/β-catenin signaling by Western blot and luciferase activity assay, in addition to cell biological behavior by Transwell and MTT assay. Dact3 expression was reduced in NSCLC tissue. Reduced Dact3 expression was correlated with lymph node metastasis and poor prognosis of NSCLC (P<0.05). In addition, Dact3 expression was negatively correlated with the c-Myb expression (R = -0.626, P<0.05). Dact3 transfection resulted in c-Myb reduced expression in NSCLC cells, as well as decreased activity of Wnt/β-catenin signaling and reduced cell invasive and proliferative capacity. siRNA-Dact3 transfection had the opposite effect. Our results indicate that Dact3 may inhibit the malignant phenotype of NSCLC through downregulation of c-Myb.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966047PMC
December 2017

DDIAS promotes invasion and proliferation of non-small cell lung cancer and predicts poor survival of lung cancer patients.

Int J Clin Exp Pathol 2017 1;10(12):11506-11515. Epub 2017 Dec 1.

Department of Pathology, The First Affiliated Hospital, The College of Basic Medicine Science of China Medical University Shenyang, China.

DNA damage-induced apoptosis suppressor (DDIAS), also called hNoxin or C11 or f82, is an anti-apoptotic protein in response to stress. The clinicopathological significance of DDIAS in non-small cell lung cancer patients is largely unknown until now. The purpose of our study is to analyze the clinicopathological association of DDIAS in NSCLC patients. We found that the positive ratio of DDIAS was significantly higher than that in the corresponding non-cancerous lung tissues (<0.001). Positive DDIAS expression correlated with larger tumor size and positive regional lymph node metastasis (=0.048 and =0.018, respectively). Online Kaplan-Meier Plotter tool analysis results and survival analysis results of our cohort revealed that both DDIAS gene level (=0.0048) and protein level (<0.001) were associated with adverse outcome in NSCLC patients for overall survival, as well as in multiple subgroups divided by different clinicopathological features. Subsequent univariate and multivariate analysis suggested that only positive DDIAS was an independent prognostic factor for overall survival (=0.018). In NSCLC cell lines, overexpression of DDIAS enhanced the ability of invasion and proliferation, whereas depleting DDIAS depressed the ability of invasion and proliferation. In conclusion, our results suggest that positive DDIAS expression may be a potent prognostic factor in NSCLC patients. DDIAS promotes proliferation and invasion in NSCLC cells and correlates with progression of NSCLC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966031PMC
December 2017

The coiled-coil domain of oncogene RASSF 7 inhibits hippo signaling and promotes non-small cell lung cancer.

Oncotarget 2017 Oct 12;8(45):78734-78748. Epub 2017 Aug 12.

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

Lung cancer is the leading cause of cancer-related deaths worldwide, and despite recent improvements in treatment patient prognosis remains dismal. In this study, we examined the role of N-terminal Ras-association domain family 7 (RASSF7) in human non-small cell lung cancer (NSCLC). We found that RASSF7 was overexpressed NSCLC tissues, which correlated with advanced TNM stage, positive lymph node metastasis, and poor prognosis. This RASSF7 overexpression promoted lung cancer cell proliferation, migration, and invasion. We also found that RASSF7 interacted with mammalian Ste20-like kinase 1(MST1) through its C-terminal coiled-coil domain to inhibit MST1 phosphorylation as well as the phosphorylation of large tumor suppressor kinase 1(LATS1) and yes-associated protein (YAP), while promoting the nuclear translocation of YAP. In addition, RASSF7 overexpression inhibited the Hippo signaling pathway both in and and promoted the expression of proteins associated with proliferation and invasion, such as connective tissue growth factor. These results suggest that targeting RASSF7 could be exploited for therapeutic benefit in the treatment of NSCLC.
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http://dx.doi.org/10.18632/oncotarget.20223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667994PMC
October 2017

Lasp1 promotes malignant phenotype of non-small-cell lung cancer via inducing phosphorylation of FAK-AKT pathway.

Oncotarget 2017 Sep 24;8(43):75102-75113. Epub 2017 Aug 24.

Department of Pathology, Basic Medicine Science and First Hospital of China Medical University, Shenyang, China.

Lasp1 (LIM and SH3 domain protein 1) promotes tumor proliferation and invasion in multiple cancer entities including non-small cell lung cancer (NSCLC). However, the molecular mechanism is uncertain to date. In the present study, using immunohistochemistry, we found that Lasp1 expression was significantly correlated with tumor size (=0.005), advanced TNM stage (=0.042), positive regional lymph node metastasis (=0.034) and poor overall survival (<0.001). Similar results were seen in patients with squamous cell lung carcinoma (=0.003 for larger tumor size, =0.017 for advanced TNM stage, =0.003 for positive lymph node metastasis and <0.001 for poor overall survival) but not in patients with lung adenocarcinoma (>0.05). Proliferation and invasion assay showed that Lasp1 dramatically promoted the ability of proliferation and invasion of NSCLC cells. Subsequent western blot results revealed that Lasp1 promoted the expression of Cyclin A2, CyclinB1, and Snail, and inhibited the expression of E-cadherin. Lasp1 directly interacted with FAK and facilitated the expression of phosphorylated FAK (Tyr397) and AKT (Ser473). Incorporation of both FAK inhibitor and AKT inhibitor counteracted the upregulating expression of Cyclin A2, CyclinB1, and Snail, and downregulating expression of E-cadherin expression induced by Lasp1 overexpression. Interestingly, inhibition of FAK signaling pathway attenuated the phosphorylation of AKT, but inhibition of AKT signaling pathway did not affect the phosphorylation of FAK. In conclusion, Lasp1 facilitated tumor proliferation and invasion of NSCLC through directly binding to FAK and enhancing the phosphorylation of FAK (Tyr397) and AKT (Ser473). Lasp1 may be a novel therapeutic target in the treatment of NSCLC patients.
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http://dx.doi.org/10.18632/oncotarget.20527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650404PMC
September 2017

TMEM17 depresses invasion and metastasis in lung cancer cells via ERK signaling pathway.

Oncotarget 2017 Sep 7;8(41):70685-70694. Epub 2017 Aug 7.

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

Transmembrane protein 17(TMEM17) is a newly identified protein, its expression pattern and clinicopathological relevance is still unclear. In this study, western blot assay was performed in 20 paired lung cancer samples and found that TMEM17 protein levels were lower in lung cancer tissues than that in the corresponding normal lung tissues (p=0.010). Immunohistochemistry staining in 143 cases lung cancer specimens also showed that TMEM17 expression in lung cancer tissues were significantly lower than adjacent normal lung tissues (35.7% 63.2%, p<0.001). And negative TMEM17 expression was significantly associated with poor histological differentiation (p=0.027), advanced TNM stages (p=0.006), positive lymph node metastasis (p=0.002) and poor prognosis (p=0.002). After overexpressing TMEM17, levels of p-ERK and its downstream molecules, p-P90RSK and Snail, were down-regulated, while levels of Occludin and Zo-1 were up-regulated, which result in the inhibition of invasion and migration ability of lung cancer cells. The effects were reversed by the incorporation of specific ERK inhibitor PD98059. In conclusion, loss of TMEM17 correlates with the development of non-small cell lung cancer (NSCLC) and predicts adverse clinical outcome of NSCLC patients. The effect of TMEM17 on inhibiting invasion and migration may attribute to restoring Occludin and Zo-1 expression through inactivating ERK-P90RSK-Snail pathway.
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http://dx.doi.org/10.18632/oncotarget.19977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642586PMC
September 2017

TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer.

Mol Carcinog 2018 02 5;57(2):159-166. Epub 2017 Dec 5.

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

TNFAIP8 is associated with prognosis of several human malignancies. However, the molecular mechanism of TNFAIP8 in lung cancer remains unknown. In our study, we found TNFAIP8 could enhance TEAD luciferase activity and inhibits the activity of Hippo pathway. TNFAIP8 also increased cyclin D1, CDK6, and decreased p27 in lung cancer cells. In addition, TNFAIP8 increased total YAP protein and promoted nuclear localization of YAP. More importantly, YAP depletion blocked the role of TNFAIP8 on cell cycle-related proteins and TEAD luciferase activity, revealing that TNFAIP8 regulates Hippo pathway in a YAP-dependend manner. Further experiments identified that TNFAIP8 depletion enhanced LATS1 phosphorylation and TNFAIP8 overexpression decreased phosphorylated LAST1 level. LATS1 siRNA treatment reversed the effects of TNFAIP8 plasmid or siRNA on cell cycle proteins. Besides, immunofluorescence and co-immunoprecipitation demonstrated the interaction between TNFAIP8 and LATS1 in H460 and H1299 cells, suggesting that TNFAIP8 regulates Hippo signaling through its interaction with LATS1. Colony formation assays and transwell assays showed that YAP or LATS1 depletion reversed the positive effect of TNFAIP8 on cell proliferation and invasion. TNFAIP8 overexpression could increase MMP-7 and TNFAIP8 depletion could decrease MMP-7 at both protein and mRNA levels, without significant changes of E-cadherin, N-cadherin, and Vimentin. Collectively, the present study provides a novel finding that TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer. TNFAIP8 may serve as a candidate biomarker for poor prognosis and a target for new therapies.
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http://dx.doi.org/10.1002/mc.22740DOI Listing
February 2018