- Primary research
- Open Access
Overexpression of SNHG12 regulates the viability and invasion of renal cell carcinoma cells through modulation of HIF1α
© The Author(s) 2019
- Received: 15 September 2018
- Accepted: 15 March 2019
- Published: 14 May 2019
Cumulative evidences demonstrated the aberrant overexpression of Small Nucleolar RNA Host Gene 12 (SNHG12) in diverse human cancer. However, the expression status and involvement of SNHG12 in renal cell carcinoma is still elusive.
The expression of SNHG12 was determined by q-PCR. The transcriptional regulation was interrogated by luciferase reporter assay. Cell viability was measured with CCK-8 kit. The anchorage-independent was evaluated by soft agar assay. Cell apoptosis was analyzed by Annexin V/7-AAD double staining. The migration and invasion were determined by trans-well assay and wound scratch closure. The in vivo tumor growth was monitored in xenograft mice model. Protein expression was quantified by immunoblotting.
SNHG12 was aberrantly up-regulated in renal carcinoma both in vivo and in vitro. High expression of SNHG12 associated with poor prognosis. Deficiency of SNHG12 significantly suppressed cell viability, anchorage-independent growth and induced apoptosis. In addition, SNHG12 silencing inhibited migrative and invasive in vitro and xenograft tumor growth in vivo. Mechanistically, SNHG12 modulated HIF1α expression via competing with miR-199a-5p, which consequently contributed to its oncogenic potential. MiR-199a-5p inhibition severely compromised SNHG12 silencing-elicited tumor repressive effects.
Our data uncovered a crucial role of SNHG12-miR-199a-5p-HIF1α axis in human renal cancer.
- Renal cancer
- Long non-coding RNA
Renal cell carcinoma (RCC) is the major form of human renal malignancies, which consists of several subtypes of cancer derived from the renal tubular epithelia . In a microscopic context, there are four major histological subtypes of RCC: clear cell (conventional RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%) . The clear cell renal cell carcinoma features richment in lipid and glycogen contents and transparency. In accordance with the Annual Cancer Statistics, approximately 340,000 new cases were diagnosed and 120,000 deaths were claimed by this disease at 2013 . Besides the regular biochemical examinations for those patients with clinical manifestations and physical examination, ultrasound, computed tomography (CT) scanning and magnetic resonance imaging (MRI) are the most common diagnostic technologies for RCC . Although it’s reported that more than 50% of the incidences of RCC relate to cigarette smoke, obesity and hypertension and are controllable with adjustments on lifestyle , the genetic aberrance in the von Hippel–Lindau (VHL) also heavily links to the etiology of RCC. VHL physiologically was identified as E3 ligase and specifically catalyzes ubiquitin attachment of hypoxia-inducible factor 1 α (HIF1α) and eventual degradation through ubiquitin–proteasome system. Compromised VHL enzymatic activity contributes to excessive transcriptional activity of HIF1α, which intrinsically dimerizes with HIF1β and translocates into nucleus to activate downstream target genes involving in diverse biological processes including neovascularization, Warburg effect and apoptosis. The sporadic mutations in mTOR and range of protein factors involving in cell epigenetics such as PBRM1, BAP1 and KDM5C have been characterized to contribute to uncontrolled cell proliferative and survival signaling in some ccRCCs as well . For the early stage RCC, nephrectomy is the first choice with curative potential, whereas advanced disease required further comprehensive managements . Owing to the intrinsic resistance, the clinical outcomes of conventional chemotherapy are very limited for RCC treatment . Anti-angiogenesis therapies such as vascular endothelial growth factor (VEGF) and mTOR inhibitors are the mainstream targeted drugs with 30–50% objective response was recorded . Nowadays, the immunotherapy targeting PD1, PD-L1 and CTL4 received increasingly interests . Long non-coding RNAs (lncRNA) are defined as RNA molecules longer than 200 bp lack of protein-coding potential, which account for approximately 80% of human transcripts . Around 300 lncRNAs were archived and curated in LncRNAdb database (http://www.lncrnadb.org) as of July 2017. The kaleidoscope of biological roles of lncRNAs have been progressively uncovered involving in complex gene regulation network . It’s been accumulatively characterized that lncRNAs target multiple transcription components either in cis- or trans-manner in eukaryotes, ranging from transcription activators, repressors, RNA polymerase II to cDNA duplex . Additionally, lncRNAs also involve in multiple stages during mRNA maturation processing across splicing, translocation, translation and decay in a manner reminiscent of the mode of action of microRNAs and snoRNAs . The importance of lncRNAs in chromatin epigenetics have been unraveled as well, which mediate imprinting, sexual chromosome silencing and telomere stabilization . Small nucleolar RNA host gene 12 (SNHG12) has been increasingly recognized involving in variety of human cancers such as human osteosarcoma cell, nasopharyngeal carcinoma cell, and human endometrial carcinoma. SNHG12 was first characterized over-expressing in osteosarcoma cells , which promoted cell proliferation and migration by up-regulating angiomotin gene expression. Zhang et al. have identified significant up-regulation of SNHG12 in brain microvascular endothelium after cerebral ischemia, which might play potential pathological roles in mediating endothelial response to ischemic stimuli . In colorectal cancer cells, Wang et al. demonstrated that long non-coding SNHG12 promoted cell growth and inhibited cell apoptosis via boosting cell cycle progression . While in triple-negative breast cancer, Wang et al. showed c-Myc-induced up-regulation of SNHG12 regulated cell proliferation, apoptosis and migration likely through MMP13 signaling . Zhu et al. revealed the potential biomarker role of SNHG12 for diagnosis and treatment purpose in lung adenocarcinoma . Wang et al. reported knockdown of SNHG12 inhibited cell growth and induced apoptosis by up-regulating miR-138 in non-small cell lung cancer . Overexpression of SNHG12 also contributed multidrug resistance through activating the MAPK/Slug pathway by sponging miR-181a in non-small lung cancer . Zhang et al. also revealed the regulatory effect of SNHG12 in gastric cancer progression by acting as a molecular sponge of miR-320 . The microRNA sponging function of SNHG12 also has been disclosed in osteosarcoma, wherein promoted tumorigenesis and metastasis by up-regulating Notch2 via competing with miR-195-5p . However, the expression status and potential involvement of SNHG12 in renal cancer has not been fully understood. Here we attempted to analyze the relative expression of SNHG12 and address its mechanistic relation to renal cancer.
The procedure involving human-related investigation was pre-approved and authorized by the Ethics Committee of The First Affiliated Hospital of China Medical University. In total, 20 renal carcinoma and adjacent benign tissues were obtained from patients who were enrolled in this study from The First Affiliated Hospital of China Medical University and informed with written consents (age 57.5 ± 9.3; male 75%). The diagnoses of renal carcinoma were validated by three experienced clinical pathologists. The fresh tissue samples were restored in liquid N2 for future analysis.
The 293T cell, renal epithelial HK-2 cell and kidney carcinoma A498, 786-0, 769-p, Caki-1, Caki-2 and ACHN were ordered and authenticated by the America Typical Culture Collection (ATCC, VA, USA). 293T cells were cultured in high-glucose DMEM medium (Gibco, CA, USA) with 10% FBS (Hyclone, MA, USA) and 1% penicillin/streptomycin (Gibco, CA, USA). All the other cells were maintained in RPMI-1640 medium (Gibco, CA, USA) supplemented with 10% fetal bovine serum and 1% P–S–G. The exponential cells were cultured in 37 °C humidified incubator with 5% CO2.
miR-199a-5p sense: 5′-CCCAGUGUUCAGACUACCUGUUC-3′;
miR-NC sense: 5′-UUCUCCGAACGUGUCACGUTT-3′.
RT-PCR primers and shRNAs oligonucleotides
Primers used for RT-PCR
Dual-luciferase reporter assay
SNHG12-mut forward: 5′-TCCCATCGGATCTCTTGTGTGGTCTTGGTGGT-3′;
SNHG12-mut reverse: 5′-ACCACCAAGACCACACAAGAGATCCGATGGGA-3′.
And co-transfected Caki-1 or ACHN cells with miR-199a-5p. Cells were harvested 48 h later and relative luciferase activities were measured with Dual Luciferase Assay System (Promega, WI, USA).
The cell lysates were prepared in RIPA lysis buffer. Equal amount of protein was subjected to SDS-PAGE resolution and transferred onto PVDF membrane on ice. The protein blots were hybridized with indicated primary antibodies immediately after blocking with 5% milk at 4 °C overnight. The second round of incubation with secondary antibody was performed at room temperature for 1 h. The target protein was visualized with the enhanced chemiluminescence method (ECL, Millipore, MO, USA).
Cell viability assay
The relative cell viability was determined by the Cell Counting Kit-8 (CCK-8 Kit, Dojindo, Dalian, China) according to the provider’s manual. 10,000 cells were plated into each well of 96-well plate in triplicate for 72 h. 10 µL of CCK-8 solution was subsequently applied into each well and allowed for reaction at 37 °C for 1 h. The absorption at 450 nm was recorded by microplate reader (Xmark, Bio-Rad, CA, USA) and relative cell count was calculated.
Soft agar assay
The colony formation capacity was determined by soft agar assay. Caki-1 and ACHN were transfected with either negative control (shNT) or SNHG12-specific shRNA (shSNHG12) and allowed by puromycin (Sigma, MO, USA) selection. The success in establishment of stable cell line was confirmed by real-time PCR. The single-cell suspension then was prepared via trypsin digestion in 2× RPMI modified medium. The cell concentration was calculated with hemocytometer and adjusted to 104 cells/500 μL. The equal volume of cell solution and 1% low-melting point agarose was mixed and laid on the top of precast 1.2% agarose cushion. The formed colonies after 2 weeks were stained with 0.05% crystal violet and counted under light microscope.
Cell apoptosis assay
The cell apoptosis was determined by Annexin V/PI staining method. Briefly, the cells were transfected as described above, and 24 h later the exponential cells were harvested with trypsin and resuspended in HEPES buffer. Double-staining with Annexin V and 7-AAD (Sigma, MO, USA) was performed at room temperature for 20 min free-of-light. The apoptotic cells were analyzed by flow cytometry (BD Biosciences, CA, USA).
Both cell migration and invasion experiments were conducted with Transwell polycarbonate membrane cell culture inserts (BD Biosciences, CA, USA). The cells were pre-starved in serum-free medium, then single-cell suspension was prepared via trypsin digestion. The cell concentration was calculated and adjusted to 1 × 105/100 μL. Each 100 μL cell solution was poured onto the upper compartment of polycarbonate Transwell chamber (Matrigel was applied for the filter for invasion assay (BD Biosciences, CA, USA)). 750 μL of complete culture medium containing 10% FBS was filled in the lower chamber as attractant. After 20 h, the free cells inside insert were completely wiped off with cotton Q-tips. The migrated/invaded cells were fixed with 4% paraformaldehyde and followed by crystal violet staining for 15 min. The cells were counted in three independent fields under optical microscope to calculate the transwell capacity.
Scratch healing assay
Scratch healing assay was employed to evaluate the cell migrative behavior. Either SNHG12-deficient or -proficient Caki-1 and ACHN cells were seeded into 6-well plate. The wound was introduced into each well using sterile pipette tips to draw a straight line. The wound-closing was regularly recorded and measured under light microscope.
To investigate the potential impact on tumor progression in vivo, we established stable SNHG12-deficient cell line in Caki-1 via puromycin selection (Sigma, MO, USA). Totally, twenty 4-week old female BALB/c-nude mice (20–22 g) were purchased from the National Laboratory Animal Center (NLAC), and equally assigned into shNT and shSNHG12 recipient groups after 1-week quarantine. All animal related experiments were performed in a SPF-class environment and the protocol was pre-approved by the Committee of Animal Care and Use of The First Affiliated Hospital of China Medical University. The animals were housed at 20–22 °C and 40–60% humidity with a 12-h light/dark cycle. Standard animal diet and water were freely available. The single-cell resuspension was prepared from log-phase cells and mixed with equal volume of Basal Membrane Extract (BD BioSciences, CA, USA). The mixture was subcutaneously injected into the lower flank of immunodeficient mice. Tumor progression was observed twice a week and volume were calculated. The animals were sacrificed at day 35 post-inoculation and xenograft tumor was resected and weighed.
RNA hybridization was applied to determined the intracellular localization of SNHG12 with Empire Genomics SNHG12 FISH probe (SNHG12-20-OR and GAPDH-20-OR, Empire Genomics, NY, USA) following the manufacturer’s recommendations. The nuclear was counter-stained with Hoechst 33342. The representative images were captured on Zeiss LSM 720 confocal microscope.
All results shown in this study was physically repeated at three times unless indicated. Data processing was facilitated by GraphPad PRISM 6.0 software. Statistical comparison was performed using ANOVA followed by Turkey’s test. The p value was calculated and p < 0.05 was considered as significantly different.
Over-expression of SNHG12 in human renal tumor
SNHG12-knockdown inhibited cell viability, anchorage-independent colony formation and induced apoptosis in renal cancer cells
SNHG12-deficiency repressed migration and invasion in renal cancer cells
SNHG12-deficiency inhibited xenograft tumor progression
SNHG12 regulated HIF1α via endogenous competition with miR-199a-5p
Hypoxia response is fundamental to tumorigenesis in renal carcinoma . The previous study by Jiang et al. showed that miR-199a-5p involved in regulation of HIF1α in human epilepsy , which prompted us to clarify this possibility in renal carcinoma. With aid of bioinformatics tools from microRNA.org, we certainly identified the putative target site of miR-199a-5p in 3′UTR region of HIF1α, and alignment between miR-199a-5p and HIF1α was illustrated in Fig. 5d. Ectopic expression of miR-199a-5p remarkably decreased endogenous HIF1α at transcript level by Q-PCR in both Caki-1 and ACHN cells (Fig. 5e). This phenotype was further confirmed at protein level as shown in Fig. 5f. The predominance of miR-199a-5p in this inhibitory action was confirmed by employment of miR-199a-5p-specific inhibitor simultaneously, which readily abolished this phenotype (Fig. 5e, f). In VHL-proficient Caki-2 cells, the low level of HIF1α was slightly stimulated by both SNHG12 and miR-199a-5p inhibitor. Notably, the negative correlation between miR-199a-5p and HIF1α and positive correlation between SNHG12 and HIF1α have been characterized in renal cancer patients (Fig. 5g). The expression status of SNHG12-miR-199a-5p-HIF1α axis was also analyzed in xenograft tumor tissue at mRNA and protein level (Fig. 5h, i), which was consistent with our previous results acquired from cell culture. In support of its mode-of-action as endogenous competing RNA, we further demonstrated the major cellular localization of SNHG12 in cytoplasm using FISH probe (Fig. 5j).
miR-199a-5p antagonism abolished SNHG12-deficiency rendered tumor suppressive effects
SNHG12 is a novel lncRNA with increasingly recognized potential involvements in diversity of human malignancies. Notably, Lan et al. demonstrated that SNHG12 promoted tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma . Consistently, in this study, we first characterized aberrant overexpression of SNHG12 in renal carcinoma both in vivo and in vitro. High expression of SNHG12 significantly associated with poor prognosis in renal cancer patients. SNHG12 knockdown remarkably inhibited cell viability, induced anoikis and stimulated cell apoptosis. Moreover, SNHG12-deficiency compromised both migrative and invasive capacity in renal cancer in vitro as well. The in vitro phenotype was further consolidated in vivo by employment of xenograft tumor mice model. Mechanistically, we elucidated that SNHG12 functioned as competing endogenous lncRNA against miR-199a-5p, and SNHG12 inversely correlated to endogenous miR-199a-5p in renal carcinomas. Noteworthily, we unraveled that HIF1α as one of the target genes of miR-199a-5p, whereas the inhibitory action was antagonized by SNHG12. The predominant role of miR-199a-5p involving in the oncogenic signaling of SNHG12 was consolidated by introducing miR-199a-5p-specific inhibitor, wherein the anti-tumor effect elicited by SNHG12-knockdown was completely abrogated. Our study for the first time highlighted the critical role of SNHG12-miR-199a-5p-HIF1α axis underlying the malignant features of renal carcinoma.
The hypoxia response is the most critical to incidence of renal carcinoma, which is frequently associated with mutations of Von Hippel–Lindau (VHL) gene. VHL physiologically was identified as E3 ligase and specifically catalyzes ubiquitin attachment of hypoxia-inducible factor 1 α (HIF1α) and eventual degradation through ubiquitin–proteasome system . The loss-of-function in VHL in this disease abolishes its intrinsic enzymatic activity as a ubiquitin E3 ligase, which in turn stabilizes HIF1α and promotes dimerization with constitutive HIF1β and translocation into nucleus, wherein HIF1α functions as the mast transcription factor to regulate diverse downstream gene and consequently contributes to the oncogenesis [29, 30]. Salama et al. demonstrated the stabilized HIF1α in VHL mutant clear cell renal cell carcinoma up-regulated sphingosine kinase-1, which in turn induced invasion in an autocrine manner and angiogenesis in a paracrine manner . Razorenova et al. reported that the apoptosis repressor with a CARD domain (ARC) gene was a direct hypoxia-inducible factor 1 target gene and promoted survival and proliferation of VHL-deficient renal cancer cells . Notably, more than 90% of the most common form of kidney cancer are associated with bi-allelic somatic mutation in VHL gene. Here we shed light on the previously unrecognized molecular mechanism underlying aberrant activation of hypoxia response in VHL-intact renal carcinoma and our data uncovered an alternative pathway through which hypoxia response was activated. Consistent with previous study that suggested miR-199a-5p negatively and post-transcriptionally regulated HIF1α in brain tissue of patients with intractable epilepsy , here we consolidated this regulatory axis in renal carcinoma which was further subjected to SNHG12 competition.
The anti-tumor properties of miR-199a-5p were increasingly recognized in range of human malignancies. For instance, Lian et al. disclosed the inhibitory effects of miR-199, miR-140 and miR-221 in Marek’s disease tumorigenesis . Chen et al. demonstrated the epigenetically suppressed miR-199/miR-214 via PSMD10/TP53/DNMT1 self-regulatory network in testicular germ cell tumor . The prognostic value of miR-199-5p along with the comprehensive microRNA expression profile has been proposed in colorectal cancer . Troppan et al. further demonstrated that miR-199a and miR-497 were associated with better overall survival in diffuse large B cell lymphoma patients due to improved chemo-sensitivity . The miR-199 has also been exploited by Callegari et al. in oncolytic adenovirus for cancer therapeutics . The results from Amr et al. implicated the potential value of miR-21 and miR-199a in early diagnosis of hepatocellular carcinoma as well . In support of the crucial anti-tumor function of miR-199a-5p, here we demonstrated that ectopic introduction of miR-199a-5p significantly suppressed the malignant behavior in renal carcinoma cells, which held great promise for the therapeutic purpose in this disease.
Noteworthily, the molecular mechanism underlying high-expression of SNHG12 in renal carcinoma was still to be elucidated in our future investigations. The previous study indicated that SNHG12 was subjected to the regulation by the transcription factor C-Myc, which was frequently over-activated in renal carcinoma . Therefore, we hypothesized that the same scenario might operate in renal carcinoma, which definitely warranted further experimental validation.
In summary, here we identified the oncogenic property of SNHG12 via miR-199a-5p-HIF1α pathway, which contributed to our comprehensive understanding of the hypoxia response in VHL-proficient renal carcinoma.
We characterize aberrant over-expression of SNHG12 in renal carcinoma, which competed with miR-199a-5p to positively regulate HIF1α. Our study unraveled a novel mechanism underlying hypoxic context in VHL-proficient renal cancer, which held potential promise for diagnostic and therapeutic exploitations.
KCZ conceived of the strategies and designed the study; CQG, ZW, DSQ, GDX, LJ, BJB, LZH, ZZ, LZL and LXK conducted experiments and analyzed data; CQG, LXK and KCZ wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
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Ethics approval and consent to participate
The tumor and adjacent normal tissue samples were collected from the First Affiliated Hospital of China Medical University with written informed consents. The experimental protocol was approved by the Ethics Committee of the First Affiliated Hospital of China Medical University.
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