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Downregulation of CENPK Suppresses Lung Adenocarcinoma by Regulating EMT

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Downregulation of CENPK Suppresses Lung Adenocarcinoma by Regulating EMT Clinical research Downregulation of CENPK suppresses lung adenocarcinoma by regulating EMT Fengwen Xie, Bin Yuan, Jichun Liu Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang Corresponding author: University, Nanchang, China Jichun Liu Department Submitted: 5 August 2020, Accepted: 28 May 2021 of Cardiovascular Surgery Online publication: 8 June 2021 The First Affiliated Hospital of Nanchang University Arch Med Sci Nanchang, China DOI: https://doi.org/10.5114/aoms/138261 E-mail: liujichun9999@126. Copyright © 2021 Termedia & Banach com Abstract Introduction: Centromere protein K (CENPK) plays a key role in regulating the assembly and function of centromeres, which in turn can affect the oc- currence and development of various tumors. However, little is known about the biological function of CENPK in lung adenocarcinoma (LUAD). Material and methods: We evaluated the relationship between CENPK ex- pression and the clinicopathological characteristics of LUAD patients via a bioinformatics method based on data taken from the TCGA database. Then, the role of CENPK in LUAD was investigated in vitro by using the hu- man LUAD cell line A549. Cell Counting Kit-8 and colony formation assays were used detect the cell proliferation ability. Wound healing and transwell assays were used to detect the cell migration and invasion ability. Epithe- lial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, Snail and vimentin) were measured by western blotting. In addition, a xenograft experiment was used to explore the function of CENPK in vivo. Results: CENPK is highly expressed in LUAD tissues and cell lines. Moreover, high expression of CENPK in LUAD is significantly associated with stage, lymph node involvement and poor survival. CENPK knockdown significantly decreases the proliferation, migration and invasion ability of A549 cells by EMT both in vitro and in vivo. Conclusions: CENPK is highly expressed in LUAD and leads to a poor progno- sis. CENPK knockdown can suppress the proliferation, migration, and inva- sion of lung cancer cells via EMT, which may be a valid target for treatment. Key words: bioinformatics, lung adenocarcinoma, CENPK. Introduction Lung cancer is one of the most common tumors worldwide, account- ing for approximately 22% of cancer-related deaths, which makes it first among cancers in terms of mortality. In the US, lung cancer accounts for 13% of all tumor types, and approximately 135,000 people die from the disease each year [1]. An epidemiological survey conducted in 2015 in China recorded 730,000 lung cancer cases and 610,000 related deaths [2]. According to the World Lung Cancer Association, lung cancer can be divided into small cell lung cancer (SCLC) and non-small-cell lung can- cer (NSCLC). NSCLC is the most common pathological type encountered in the clinic, accounting for 85% of new cases each year [3]. With the promotion of smoking bans, the pathological spectrum of NSCLC has changed dramatically; approximately 40–60% of new NSCLC cases are Fengwen Xie, Bin Yuan, Jichun Liu lung adenocarcinoma (LUAD), occurring especially including wound healing, fibrosis and cancer de- among nonsmoking women in East Asia [4]. LUAD velopment [21]. According to the different physi- originates from small alveolar epithelial cells of ological environments, EMT can be divided into the type II airways and is characterized by easy three subtypes, including type 1, type 2 and type 3 recurrence and metastasis [5]. The disease stages [22]. Type 3 is the most studied type at present, of LUAD play an important guiding role in formu- which is closely related to the growth and metas- lating specific treatment plans for patients with tasis of malignant tumor cells [22]. A number of LUAD. For the treatment of lung cancer, in addition studies have shown that EMT occurs during the in- to surgery, radiotherapy and chemotherapy, tar- vasion and metastasis of lung cancer, liver cancer, geted therapy and immunotherapy have become breast cancer, and other tumors [23–25]. The main the new development direction of lung cancer functions of EMT include [26]: (1) the loss of po- treatment. For example, studies on the third-gen- larity of epithelial cells, the decrease of the ability eration epidermal growth factor receptor (EGFR) of tight connection between cells, the long spindle mutation inhibitor osimertinib show that the me- shape and the loose arrangement of cells, similar dian progression-free survival (PFS) of lung cancer to the characteristics of mesenchymal cells. (2) The patients treated with osimertinib is 10.1 months, changes of protein expression, down-regulation of which is significantly longer than that of patients the expression of E-cadherin, β-catenin, cytokera- treated with chemotherapy (median PFS is 4.4 tin 8 (CK8), cytokeratin 18 (CK18), up-regulation of months) [6, 7]. Immunotherapy was selected as the the expression of mesenchymal marker proteins, benchmark achievement of medical progress in such as N-cadherin, vimentin and fibronectin. 2016 by the American Society of Clinical Oncology (3) When the tight connection between epithelial (ASCO), which is the most cutting-edge in the field cells decreases and transforms into stromal cells, of cancer treatment [8]. At present, immunother- their biological behaviors change when their in- apeutic drugs for lung cancer are mainly immune vasion ability is improved. Proteolytic enzymes checkpoint inhibitors, such as programmed cell degrade the cell basement membrane, allowing death protein-1/programmed cell death ligand 1 cells to invade the extracellular matrix. Therefore, (PD-1/PD-L1) [9]. A number of large-scale clinical the cells have a strong ability of invasion and me- trials have shown that compared with chemother- tastasis. Once metastasis occurs, cancer cells can apy patients, the overall survival of lung cancer escape chemical treatment, which leads to the de- patients treated with PD-1/PD-L1 immune check- teriorating prognosis of cancer patients [26]. point inhibitors is significantly longer [10, 11]. Al- In this study, the relationship between the ex- though technological progress has improved the pression of CENPK and LUAD was investigated diagnosis and treatment of LUAD, the 5-year sur- using bioinformatics methods and in vitro/vivo vival rate is only 10–15% [12]. Therefore, the iden- experiments. tification of prognostic markers and therapeutic targets for LUAD is a topic of intense research in Material and methods lung cancer research. The Cancer Genome Atlas (TCGA) database Centromere protein K (CENPK) belongs to the analysis mitochondrial protein family and can be recruited to centromeres during cell division and participate The TCGA database (https://cancergenome.nih. in the processes of centromere assembly, mitosis gov/) is a research project jointly developed by the and chromosome separation [13–15]. An increas- National Cancer Institute and the National Human ing body of evidence has implicated dysregulation Genome Research Institute that aims to discover or dysfunction of CENPK in cancer progression. gene mutations and signaling pathways related to Research shows that CENPK is an oncogene that tumor occurrence, development, and prognosis at can promote cancer cell proliferation and metas- the molecular level through genome-wide analy- tasis in liver cancer and ovarian cancer [16–18]. sis of tumor specimens [27]. Transcript and clin- Overexpression of CENPK was associated with ical data from LUAD and normal tissue samples poor outcomes in patients with triple-negative were obtained from the TCGA database, which is breast cancer [19]. However, the biological func- public and can be downloaded free of charge, with tions of CENPK in LUAD still remain unclear. confirmation that all relevant informed consent Epithelial-mesenchymal transition (EMT) refers has been supplied. Clinical information, including to the transformation of differentiated epithelial patient age and sex, disease stage, histological cells into mesenchymal cells under specific phys- type, tumor-node-metastasis (TNM) classification, iological and pathological conditions, and is an in- follow-up time, and survival status, was extracted herent biological process of cells existing in various from the data of 515 LUAD patients, from which tissue types and development stages [20]. EMT is 515 tumor tissues and 59 adjacent normal tissues closely related to a variety of biological processes, were obtained. 2 Arch Med Sci Downregulation of CENPK suppresses lung adenocarcinoma by regulating EMT Oncomine database analysis Quantitative real-time PCR (qRT-PCR) The Oncomine database (https://www.onco- Total RNA was extracted from cells using TRIzol mine.org/) is currently the world’s largest tumor reagent (Invitrogen) and reverse-transcribed to gene chip database and integrated data mining cDNA using the EasyScript First-Strand cDNA Syn- platform and can be used to mine cancer gene-re- thesis SuperMix Kit (TransGen Biotech). QRT-PCR lated information [28]. The mRNA expression level was performed with the StepOnePlus Real-Time of CENPK in LUAD and other cancers was detected PCR System (Applied Biosystems) and Fast Start through Oncomine database analysis. P-value < Universal SYBR Green Master Mix (Takara). The 0.05, fold change > 2 and top 10% gene rank were relative quantification of CENPK to the internal selected as thresholds for comparisons between control (GAPDH) was calculated using the 2−ΔΔCt tumor and normal samples. method. The primers for qPCR are listed in Table
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