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INAVA Promotes Aggressiveness of Papillary Thyroid Cancer By

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INAVA Promotes Aggressiveness of Papillary Thyroid Cancer By Guan et al. Cell Biosci (2018) 8:26 https://doi.org/10.1186/s13578-018-0224-4 Cell & Bioscience RESEARCH Open Access INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression Hongyu Guan1†, Yan Guo1†, Liehua Liu1†, Runyi Ye2, Weiwei Liang1, Hai Li1, Haipeng Xiao1 and Yanbing Li1* Abstract Background: Innate immunity activator (INAVA) has been shown to be elevated in lung adenocarcinoma. However, its expression pattern and function in papillary thyroid cancer (PTC) are unknown. This study aimed to identify the clinical, biological, and mechanistic impacts of INAVA on PTC. Methods: Using The Cancer Genome Atlas dataset, real time PCR, and immunohistochemistry, the expression of INAVA in PTC was analyzed. Gain- and loss-of-function assays were performed to investigate the role of INAVA in PTC cell invasion, migration, and metastasis. We explored the molecular mechanisms underlying the roles of INAVA in PTC cells using transcriptome resequencing, real time PCR, western blotting and immunohistochemistry. Results: We found that INAVA expression was signifcantly upregulated in PTC and was signifcantly associated with lymph node metastasis. Loss- and gain-of-function experiments demonstrated that INAVA promoted the aggres- sive phenotype of PTC cells in vitro and in vivo. Mechanistic study suggested that upregulation of INAVA resulted in elevated fbroblast growth factor 1 (FGF1), which in turn increased the expression level of matrix metalloproteinases 9 (MMP9). We further identifed that the level of INAVA was positively correlated with the levels of FGF1 and MMP9 in clinical PTC specimens. Conclusion: These data establish a novel role for INAVA in promoting PTC progression and suggest that INAVA may represent a therapeutic target for the disease. Keywords: INAVA, Papillary thyroid cancer, Invasion, MMP9, FGF1 Background [4, 5]. Tus, a good understanding of the molecular alter- Tyroid cancer is the most common type of endocrine- ations responsible for aggressive behavior of PTC is still related malignancy and shows rapidly increasing inci- imperative. dences during the past decades [1]. Papillary thyroid Tumor metastasis is a multistep process during which cancer (PTC) is the most common form of thyroid can- a subset of cancer cells disseminate from the site of a cer, representing 70–80% of all thyroid cancer [2]. In primary tumor and establish secondary tumors at dis- most cases, patients with PTC follow an indolent course tant sites [6]. Matrix metalloproteinases (MMPs) are and have excellent prognosis [3]. However, extrathyroidal proteolytic enzymes responsible for remodeling extra- extension and distant metastasis are extremely important cellular matrix (ECM) in many physiological and path- risk factors for PTC and are still major clinical challenges ological processes [7]. Moreover, besides its role in degradation of ECM molecules, MMPs play important roles in multiple aspects of cancer progression, includ- *Correspondence: [email protected] †Hongyu Guan, Yan Guo, and Liehua Liu contributed equally to this work ing tumor growth, almost all metastatic steps, and 1 Department of Endocrinology and Diabetes Center, The First angiogenesis [8, 9]. MMP9, one of the best character- Afliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, ized members in MMP family, is well known to degrade Guangzhou 510080, Guangdong, China Full list of author information is available at the end of the article ECM and is closely related to the cancer invasion and © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Guan et al. Cell Biosci (2018) 8:26 Page 2 of 14 metastasis [10]. In PTC, Ahmed et al. showed that silenc- incubated with primary antibodies against INAVA and ing of FoxM1 inhibited migration and invasion of PTC fbroblast growth factor 1 (FGF1) (Abcam, Cambridge, cells via decreasing the expression levels of MMP9 and MA), MMP9 (Cell Signaling Technology). Te IHC stain- MMP2 [11]. Moreover, the expression level of arachido- ing was evaluated as described in our previous study [16]. nate 5-lipoxygenase (ALOX5) was upregulated in PTC Briefy, the intensity of staining was scored as 0 (no stain- and it promoted PTC cell invasion through increased ing), 1 (weak staining = light yellow), 2 (moderate stain- secretion of MMP9 [12]. ing = yellow brown), or 3 (strong staining = brown). Te Innate immunity activator (INAVA, also named chro- proportion of tumor cells was scored as 0 (no positive mosome 1 open reading frame 106) is a protein coding tumor cells), 1 (< 10% positive tumor cells), 2 (10–50% gene known to be a risk locus for Crohn’s disease [13, 14]. positive tumor cells), or 3 (> 50% positive tumor cells). Notably, a global analysis of chromosome 1 genes among Te staining index (SI) was calculated by multiplying patients with lung adenocarcinoma found that INAVA the intensity and proportion score. An SI score of ≥ 4 was upregulated at four stages of lung adenocarcinoma, was regarded as tumors with high expression and ≤ 3 as implicating that INAVA may play important roles in can- tumors with low expression. cer development and progression [15]. Nevertheless, the role of INAVA has not been investigated in malignant Vectors and retroviral infection diseases. Here, we investigated the expression pattern INAVA construct was generated by sub-cloning PCR- of INAVA in human PTC and attempted to explore the amplifed full-length human INAVA cDNA into pQCXIP molecular mechanisms mediating the possible oncogenic (Clontech, Mountain View, CA). Te pRS-INAVA-shR- functions of INAVA. NAs (TR306059) were purchased from OriGene (Rock- ville, MD). Tese plasmids were transfected into PT67 Methods cells (Clontech) using Lipofectamine 3000 (Invitrogen, Cell lines and reagents San Diego, CA). After transfection, the PT67 cells were Te human PTC cell line K1 was purchased from the cultured for 48 h. Ten, the supernatant was harvested, European Collection of Cell Cultures (ECACC, Salis- passed through a 0.45-μm flter and incubated with the bury, UK), and the TPC1 cell line was provided by Prof. indicated cells along with polybrene (8 μg/mL). Subse- Haixia Guan (China Medical University, China). All cell quently, stable cell lines were selected with 0.5 μg/mL of lines were authenticated by short tandem repeat (STR) puromycin for 2 weeks [17]. DNA profling and were verifed to be mycoplasma-free. Te cells were cultured in Dulbecco’s modifed Eagle’s RNA extraction and real-time reverse medium (DMEM) (Gibco, Grand Island, NY) containing transcription-polymerase chain reaction (RT-PCR) 10% fetal bovine serum (FBS; Gibco), 100 U/mL peni- Total RNA was extracted using TRIzol (Invitrogen). RT cillin (Gibco), and 100 mg/mL streptomycin (Gibco) at was carried out with the Moloney murine leukemia virus 37 °C in a 5% CO2 humidifed incubator. reverse transcriptase (MMLV-RT) (Promega, Madison, WI) using 1 μg of total RNA as the template. Real-time Patients and tissue specimens RT-PCR detection was performed using SYBR Premix Ex Te 112 cases of parafn-embedded PTC and 16 pairs of Taq (TaKaRa, Dalian, China) on a 7500 system (Applied fresh PTC and their adjacent noncancerous thyroid tis- Biosystems, Carlsbad, CA). Glyceraldehyde-3-phosphate sues were histopathologically and clinically diagnosed dehydrogenase (GAPDH) was used as an internal con- at the First Afliated Hospital of Sun Yat-sen University trol. Te following primers were used: MMP9 forward, from 2011 to 2016. Te 16 pairs of fresh tissues were 5′-ACGACGTCTTCCAGTACCGA-3′ and reverse, collected from 16 patients, and then were frozen and 5′-TTGGTCCACCTGGTTCAACT-3′; FGF1 forward, stored in liquid nitrogen until used. Te pathology of all 5′-TGTGGAGAGAGGTACAGCCC-3′ and reverse, specimens was confrmed by two pathologists. Informed 5′-AAGGTGGTGATTTCCCCTTC-3′; GAPDH for- consents from patients and ethics approval from the ward, 5′-GACTCATGACCACAGTCCATG-3′ and Institutional Research Ethics Committee were obtained. reverse, 5′-AGAGGCAGGGATGATGTTCTG-3′. Te relative expression levels were determined using the 2 −ΔΔCt Immunohistochemistry (IHC) method. Each sample was analyzed three times in triplicate. Parafn sections were deparafnized with xylene, rehy- drated with alcohol, subjected to antigen retrieval in Western blotting (WB) analysis sodium citrate bufer (10 mM, pH 6.0) and blocked in Te indicated cells were harvested and lysed using PBS containing 1% (wt/vol) bovine serum albumin (BSA; RIPA lysis bufer (Termo Fisher Scientifc, Waltham, Sigma-Aldrich, St. Louis, MO). Ten the sections were MA). Te concentration of protein was determined by Guan et al. Cell Biosci (2018) 8:26 Page 3 of 14 the bicinchoninic acid assay (BCA; Termo Fisher Sci- (HE) [18]. Microscopic evaluation was carried out using entifc). Equal amounts of proteins were separated by the BX51 Olympus microscope (Olympus, Tokyo, Japan) sodium dodecyl sulfate–polyacrylamide gel electropho- and photographs were obtained. Metastasis area was cal- resis (SDS-PAGE) gels and then transferred to
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