Publications by authors named "Xuezhu Rong"

13 Publications

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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

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

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

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

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

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

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

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

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