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Inhibition of EFEMP2 Suppresses the Cell Proliferation of Cervical Cancer Cells Via AKT Signaling

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Inhibition of EFEMP2 Suppresses the Cell Proliferation of Cervical Cancer Cells Via AKT Signaling Research Article Journal of Gynecological Oncology Published: 10 Oct, 2019 Inhibition of EFEMP2 Suppresses the Cell Proliferation of Cervical Cancer Cells via AKT Signaling Yanfei L1,2, Haoying P2, Jin Z2, Zhongping N1* and Junwei S1,3* 1Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, China 2School of Medical Technology, Shanghai University of Medicine and Health Sciences, China 3Eastern Hospital, Tongji University, China Abstract Objectives: Cervical cancer is the most common gynecological cancer in the world and is one of the leading causes of cancer related death among women. EFEMP2, an extracellular matrix protein that could be easily detected in serum, plays key roles in several cancers formation and progression. However, its role in cervical cancer remains to be determined. Methods: We have analyzed differentially expressed genes between Long-Term Survivors (LTSs) and Short-Term Survivors (STSs) using edgeR. The EFEMP2 shRNA plasmids were prepared and the EFEMP2 knockdown cervical cancer cell lines were constructed. The functions of EFEMP2 on cervical cancer were evaluated in vitro and in vivo and the molecular mechanism was investigated by western blotting, etc. Results: The genes associated with the Extracellular Matrix (ECM) were significantly down- regulated in LTSs group compared with STSs. Low expression of EFEMP2 was positively associated with longer survival of cervical cancer patients. Knockdown of EFEMP2 not only suppressed the cell proliferation of cervical cancer cells in vitro, but inhibited the tumor growth in vivo. Moreover, EFEMP2 knockdown suppressed the expression of several genes related to promoting-proliferation by inhibiting AKT signaling. Conclusion: EFEMP2 functions as an oncogene to promote cell proliferation of cervical cancer, and it is a promising biomarker and therapy target for human cervical cancer. OPEN ACCESS Keywords: Extracellular Matrix; EFEMP2; Cervical Cancer; Tumor Biomarkers; AKT Signaling *Correspondence: Junwei Shen, Shanghai University of Introduction Medicine and Health Sciences affiliated Cervical cancer is the second most common cancer among global females, which ranks next Zhoupu Hospital, Shanghai, 201318, only to breast cancer and becomes one of the main death causes for females [1]. 527,600 new cases China, were added and the death toll reaches 265,700 in 2012 [1]. It causes serious harm on developing E-mail: [email protected] countries particularly [1]. For example, cervical cancer is the main reason to cause female death in Received Date: 06 Sep 2019 Africa, Central America and Northeast Asia [2]. Cervical cancer is the gynecological oncology with Accepted Date: 24 Sep 2019 the highest morbidity and mortality in China [3]. There were 98,900 new cases, wherein 30,500 cases Published Date: 10 Oct 2019 were died in China in 2015 [3]. Although the cervical cancer screening has been applied for decades, Citation: 5-year survival rate of cervical cancer is not improved remarkably [1]. Actually, the research on Yanfei L, Haoying P, Jin Z, Zhongping cervical cancer has been developed early, since the first immortalized human cell line-Hela is taken N, Junwei S. Inhibition of EFEMP2 from a black woman with cervical cancer [4]. However, the pathogenesis of cervical cancer and its Suppresses the Cell Proliferation molecular mechanism remains to be determined. It is of great significance to disclose the molecular of Cervical Cancer Cells via AKT mechanism for tumor diagnosis and treatment. For example, cell cycle regulating protein CDK4 Signaling. J Gynecol Oncol. 2019; 2(2): promotes tumorigenesis and growth [5]. Palbociclib, a newly-approved selected CDK4 inhibitor, 1015. has remarkable treatment effect on advanced breast cancer [6]. Therefore, it is very necessary to study a novel and effective biomarker or therapy target related with tumorigenesis and progression Copyright © 2019 Junwei S. This is an of cervical cancer. open access article distributed under the Creative Commons Attribution The Extracellular Matrix (ECM) is a highly dynamic fundamental structure that is present in License, which permits unrestricted all tissues [7-9]. The ECM serves not only as the scaffold upon which tissues are organized but use, distribution, and reproduction in also provides critical biochemical and biomechanical signals that regulate cell growth, survival, any medium, provided the original work migration, differentiation and immune function [8,10,11]. Similarly, besides functioning as an integral feature, the ECM actively contributes to the formation and progression of cancer [12,13]. is properly cited. Remedy Publications LLC. 1 2019 | Volume 2 | Issue 2 | Article 1015 Junwei S, et al., Journal of Gynecological Oncology For instance, pancreatic cancer patients usually show a marked Plasmids transfection and lentivirus infection stromal desmoplasia which associates with rapid progression and The shRNAs target human EFEMP2 sequences were obtained poor prognosis [14]. Similarly, MMPs, the matrix remodeling from Sigma-Aldrich (Table 1). For viral packaging, 293T cells were genes, are predictive of a poor prognosis for breast cancer patients transfected with pLVX-shRNA2, psPAX2 and pMD2.G plasmids [15]. Laminins, one of the main components of ECM, impact the using the FuGene HD transfection reagent (Roche Diagnostics, migration and functions of immune cells [16]. Although the ECM Basel, Switzerland). Forty eight hours after transfection, the virus- has explained many features of tumor, there are many unanswered containing medium was harvested and filtered to remove cell debris. questions with regard to how the ECM and its biophysical properties The cervical cancer cells were infected with virus-containing medium influence tumor progression. for 24 h then replaced fresh medium. The infected cells displayed Fibrous is an ECM glycoprotein, consisting of epidermal growth green fluorescence. Five days after infection, the stably infected factor EGF-like domain, calcium combined with EGF-like domain clones were selected with Flow Cytometer (BD FACS AriaII, BD and unique fibrin C terminal domain [17]. The fibrous not only Biosciences, Franklin Lakes, NJ).The selected stably infected clones stabilizes the ECM structure, but also interacts with cells and control were incubated for further study. the growth of normal and malignant cells [18]. For example, Yasmin Cell proliferation assay et al. [19] reported that Fibulin1 plays an extremely important role For the proliferation assay, Hela and Siha cells were seeded into in determining aortic stiffness and its modification with age could 96-well plates (1000 cells/well) and were detected using CCK8 at 12 h, underpin aortic stiffening. Fibulin-2 is critically associated with breast 36 h, 60 h and 84 h. In brief, 10 µl cell counting Kit-8 reagent (CCK8) cancer progression [20]. EGF-containing fibulin-like extracellular (Dojindo, Kumamoto, Japan) was added into each well of the 96-well matrix protein 2 (EFEMP2, called as Fibulin-4), a fibulin member, is plate. Then the plate was incubated at 37°C for 2 h. The absorbance at proved to have an indispensable role in the formation of collagenous 450 nm was subsequently detected with SpectraMax M5 (Molecular fiber and elastic fiber [21]. It is reported that the mice with knockout Devices, Silicon Valley, CA). EFEMP2 lack elastic fiber and are dead during the perinatal period [22]. It is illustrated that EFEMP2 is markedly increased in colorectal Quantitative Reverse Transcription Polymerase Chain cancer tissue and could function as serum biomarker for the early Reaction (qRT-PCR) detection of colorectal cancer [23]. Additionally, the high expression qRT-PCR was performed to detect the transcriptional level of of EFEMP2 can remarkably promote the proliferation and invasion EFEMP2 according to the manufacturer’s protocol (Thermo Fisher of glioma [24]. Although the functions of EFEMP2 have been Scientific, Waltham, MA, USA). Briefly, total cellular RNA was investigated in several human cancers, its role involved in cervical extracted from Hela and Siha cells with TRIzol reagent (Gibco; Thermo cancer remains to be further determined. Fisher Scientific, Inc.). Then the TRIzol mixed with chloroform (in Materials and Methods a 5:1 ratio) followed by centrifugation at 12,000 rpm for 15 min at 4°C. The supernatant was blended with isopropanol (in a 1:1 ratio) Cervical squamous cell carcinoma data in TCGA for 30 min at room temperature and then centrifuged at 10,000 Clinical data and RNA-seq data of primary CESC samples in The rpm for 10 min at 4°C. The RNA precipitate was washed with 75% Cancer Genome Atlas (TCGA) were downloaded from Genome Data ethanol and solubilized with Diethypyrocarbonate (DEPC) treated Commons (https://portal.gdc.cancer.gov). Long-Term Survivors water. The RNA quantity and quality was measured at 260 nm/280 (LTSs) were defined as patients with overall survival of >5 years from nm using the NanoDrop ND-1000 (Thermo Fisher Scientific, Inc.). surgery, Short Term Survivors (STSs) as patients with survival >30 Single stranded cDNA was prepared using a Reverse Transcription days and <5 year from surgery, to exclude patients of perioperative System (Baosheng, Dalian, China) following the operation manual. mortalities. mRNA level of EFEMP2 was determined with a SYBR Green qPCR Mix kit (Baosheng). qPCR was performed in an Applied Biosystems Differentially expressed genes analysis and Gene Set 7300 sequence detection system (Applied Biosystems, Thermo Enrichment Analysis
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