European Review for Medical and Pharmacological Sciences 2019; 23: 6186-6193 Downregulation of lncRNA SNHG7 inhibits proliferation and invasion of nasopharyngeal carcinoma cells through repressing ROCK1

L. WANG1,2, T. XU3, X. CUI4, M. HAN2, L.-H. ZHOU2, Z.-X. WEI2, Z.-J. XU2, Y. JIANG2

1Department of Otorhinolaryngology, Qilu Hospital of University, , 2Department of Otorhinolaryngology, The Affiliated Hospital of University, Qingdao, China 3Department of Orthidontics, The Affiliated Hospital of Qingdao University, Qingdao, China 4Department of Otorhinolaryngology, Qingdao Women and Children’s Hospital Affiliated to Qingdao University, Qingdao, China Lin Wang and Tao Xu contributed equally to this work

Abstract. – OBJECTIVE: Recent studies have Key Words: revealed the important role of long noncoding Long noncoding RNA, SNHG7, Nasopharyngeal RNAs (lncRNAs) in the progression of tumori- carcinoma, ROCK1. genesis. This study aimed to identify the bio- logical function of lncRNA small nucleolar RNA host gene 7 (SNHG7) in the progression of naso- Introduction pharyngeal carcinoma (NPC). PATIENTS AND METHODS: LncRNA SNHG7 Nasopharyngeal carcinoma (NPC) is one of expressions in NPC cell lines and 50 paired NPC tissue samples were detected by Real-time the most common head and neck epithelial can- quantitative polymerase chain reaction (RT-qP- cers with high morbidity in Southern China and CR). Transwell assay, wound healing assay and Southeast Asia1. With the advances made in inten- proliferation assay were conducted to evaluate sity-modulated radiotherapy and combined che- the in vitro function of SNHG7 in NPC cells. Xe- moradiotherapy, the prognosis for patients with nograft model was established for determining local and regional NPC has been significantly the in vivo effect of SNHG7 on tumor formation improved. However, metastatic rate remains high and metastasis of NPC. The underlying mech- anism of SNHG7 in mediating the progression in NPC patients, which is the leading cause of tre- of NPC was explored by RT-qPCR and Western atment failure and cancer-related death in NPC, 2,3 blot. with a median survival about 12 months . The- RESULTS: SNHG7 expression was remarkably refore, clarifying the molecular mechanisms un- downregulated in NPC tissues compared with derlying NPC is urgently required to promote the that in adjacent normal samples. Knockdown of development of effective individualized therapy SNHG7 attenuated proliferation, invasion and and improve the clinical outcomes of NPC pa- migration of NPC cells. Moreover, tumor size tients. With the development of high-throughput and the number of metastatic nodules were re- duced in mice administrated with NPC cells sequencing and microarrays, researchers have di- transfected with sh-SNHG7. Knockdown of SN- scovered that more than 90% of mammalian ge- HG7 downregulated ROCK1 at mRNA and pro- nome can be transcribed into noncoding RNAs tein level. Besides, the expression of ROCK1 in (ncRNAs). Long noncoding RNAs (lncRNAs), tumor tissues was positively correlated to SN- one subgroup of ncRNAs in over 200 nt long, are HG7 expression. important clusters of transcripts with little pro- CONCLUSIONS: Knockdown of SNHG7 inhib- tein-coding potential. Recently, evidence proved its migration, invasion and proliferation of NPC cells through downregulating ROCK1, which that lncRNAs are important regulators in many mayRETRACTED offer a new therapeutic intervention for biological behaviors, including carcinogenesis. NPC patients. For example, lncRNA TP73AS1 dramatically

6186 Corresponding Author: Yan Jiang, MD; e-mail: [email protected] LncRNA SNHG7 inhibits the progression of nasopharyngeal carcinoma promotes cell apoptosis and depresses cell proli- SNHG7 was amplified and inserted into pcD- feration in colorectal cancer by functioning as a NA3.1 (Invitrogen, Carlsbad, CA, USA). Cell competing endogenous RNA sponging miR103 to transfection was conducted with Lipofectamine modulate the expression of PTEN (gene of pho- 2000 (Invitrogen, Carlsbad, CA, USA). Tran- sphate and tension homology deleted on chromo- sfection efficacy at 48 h was detected by Real-ti- some ten)5. Long non-coding RNA ZFAS1 promo- me quantitative polymerase chain reaction (RT- tes nasopharyngeal carcinoma through activating qPCR). Wnt/beta-catenin pathway6. In addition, lncRNA CDKN2BAS promotes cell growth and migration RNA Extraction and RT-qPCR in hepatocellular carcinoma through miR-153-5p/ Total RNA from tissues and cells were ex- ARHGAP18 signaling pathway7. However, the tracted using TRIzol reagent (Invitrogen, Car- potential role of lncRNA small nucleolar RNA lsbad, CA, USA). The total RNA was reversely host gene 7 (SNHG7) in the development of NPC transcribed to complementary deoxyribose nu- remains unexplored. In the present study, expres- cleic acids (cDNAs) through reverse Transcrip- sion level of lncRNA SNHG7 was remarkably tion Kit (TaKaRa Biotechnology Co., Ltd., Da- upregulated in NPC samples. Moreover, fun- lian, China). Thermocycling conditions were as ctional experiments revealed that knockdown of follows: 30 s at 95°C, 5 s at 95°C and 35 s at 60°C, SNHG7 depressed cell proliferation, invasion and for 40 cycles. Following were the primers used for migration in NPC. Furthermore, we discovered RT-qPCR: SNHG7, forward: 5′- GTGACTTCGC- that lncRNA SNHG7 exerted its role in the pro- CTGTGATGGA-3′ and reverse: 5′-GGCCTCTA- gression of NPC by upregulating ROCK1. TCTGTACCTTTATTCC-3′; glyceraldehyde 3-phosphate dehydrogenase (GAPDH), forward: 5′-CCAAAATCAGATGGGGCAATGCTGG-3′ Patients and Methods and reverse: 5′-TGATGGCATGGACTGTG- GTCATTCA-3′. 2-ΔΔCt method was utilized for Tissue Specimens calculating relative expression. Paired NPC tissues and adjacent non-tumor tissues (≥ 5 cm away from the tumor edge) were Western Blot surgically resected from 50 NPC patients under- Total proteins were extracted from cells via ra- going surgery from February 2016 to December dioimmunoprecipitation assay (RIPA) buffer and 2018 in the Affiliated Hospital of Qingdao Uni- quantified by bicinchoninic acid (BCA) protein versity. The Ethics Committee of the Affiliated quantification kit (Beyotime, Shanghai, China). Hospital of Qingdao University approved this stu- The target proteins were separated by sodium do- dy protocol, and all participants provided written decyl sulphate-polyacrylamide gel electrophore- informed consents. sis (SDS-PAGE). Protein samples were loaded on the polyvinylidene difluoride (PVDF) membrane Cell Lines (Millipore, Billerica, MA, USA). Membranes were Human NPC cell lines CNE2, CNE1, 5-8F and blocked in 5% skim milk and incubated with pri- 6-18B and immortalized normal nasopharynge- mary antibodies (rabbit anti-GAPDH and rabbit al epithelial cell line NP69 were offered by the anti-ROCK1) and secondary antibodies. Finally, Chinese Academy of Science (Shanghai, China). the Pierce (Rockford, IL, USA) enhanced chemi- Cells were cultured in Roswell Park Memorial luminescence (ECL) was utilized for visualizing Institute-1640 (RPMI-1640) (HyClone, South Lo- Western blotting substrate immunoreactive bands. gan, UT, USA) containing 10% fetal bovine se- rum (FBS) (Gibco, Rockville, MD, USA) and 1% Cell Proliferation Assay penicillin (epidermal growth factor was applied Cell proliferation was monitored every 24 h by for culturing NP69 cells). Cells were maintained cell counting kit-8 (CCK-8) assay. Spectrophoto- in an incubator with 5% CO2 at 37°C. meter (Thermo Scientific, Waltham, MA, USA) was utilized to measure the absorbance at 450 nm. Cell Transfection Lentivirus expressing short-hairpin RNA Wound Healing Assay (shRNA) directed against SNHG7 was provided Cells seeded into 6-well plates, were cultured by GenePharmaRETRACTED (Shanghai, China). Complemen- in Roswell Park Memorial Institute 1640 (RPMI- tary deoxyribose nucleic acid (cDNA) encoding 1640) medium overnight. After scratched with

6187 L. Wang, T. Xu, X. Cui, M. Han, L.-H. Zhou, Z.-X. Wei, Z.-J. Xu, Y. Jiang a plastic tip, cells were cultured in serum-free the number of metastatic nodules in the lung was (RPMI-1640). Wound closure was viewed at the counted. The animal experiments were approved appointed time points. Each assay was indepen- by the Animal Ethics Committee of Qingdao Uni- dently repeated for three times. versity (Qingdao, China).

Matrigel Assay Statistical Analysis 24 h after transfection, 2 × 105 cells suspended Statistical analysis was conducted by Statisti- in 100 µL of serum-free Roswell Park Memorial cal Product and Service Solutions (SPSS) 18.0 Institute-1640 (RPMI-1640) were applied on the (SPSS Inc., Chicago, IL, USA). Chi-square test, top chamber of an 8-μm culture inserts (Corning, Student t-test and Kaplan-Meier method were se- Corning, NY, USA) pre-coated with 50 µg Matri- lected when appropriate. Data were presented by gel (BD Biosciences, Franklin Lakes, NJ, USA). mean ± SD (Standard Deviation). It was conside- Roswell Park Memorial Institute-1640 (RPMI- red statistically significant when p<0.05. 1640) containing 20% fetal bovine serum (FBS) was added in the bottom chamber. 24 h later, the- se inserts were treated by methanol for 30 min Results and stained by hematoxylin for 20 min. An inver- ted microscope (×40) (Nikon, Tokyo, Japan) was Expression Level of SNHG7 in utilized for counting penetrating cells in three NPC Tissues and Cells random fields. First, RT-qPCR was conducted for detecting SNHG7 expression in 50 paired NPC tissues and Xenograft Model 4 NPC cell lines. The result indicated that SNHG7 For the tumor formation assay, transfected 5-8F was significantly upregulated in NPC tissue sam- cells were subcutaneously injected into NOD/ ples than that in adjacent tissues (Figure 1A). SCID mice (6 weeks old). Tumor diameters were Compared with the expression in NP69, SNHG7 detected every 5 days after inoculation. Tumor level was significantly higher in NPC cells (Figu- volume was calculated as the formula (volume= re 1B). length × width2 × 1/2). The mice were sacrificed, and tumors were extracted after 4 weeks. For the Knockdown of SNHG7 Repressed Cell tumor metastasis assay, transfected 5-8F cells Proliferation in Vitro were injected into tail vein of NOD/SCID mice According to SNHG7 expression in cancer (6 weeks old). The mice were sacrificed, and the cells, 5-8F cells were selected for conducting lung tissues were extracted after 4 weeks. Next, SNHG7 knockdown model. The SNHG7 shR-

Figure 1. Expression levels of SNHG7 were upregulated in NPC tissues and cell lines. A, SNHG7 expression significantly increased in NPC tissues compared with adjacent tissues. B, Expression levels of SNHG7 relative to GAPDH were determined in theRETRACTED human NPC cell lines and immortalized normal nasopharyngeal epithelial cell line (NP69) by RT-qPCR. Data are presented as the mean ± standard error of the mean. *p<0.05.

6188 LncRNA SNHG7 inhibits the progression of nasopharyngeal carcinoma

NA (sh-SNHG7) and the empty vector (EV) Knockdown of SNHG7 Repressed were synthetized and transfected into 5-8F cel- Cell Migration and Invasion in Vitro ls. Transfection of sh-SNHG7 markedly down- Wound healing assay found that knockdown regulated SNHG7 level in 5-8F cells (Figure of SNHG7 inhibited migration of NPC cells (Fi- 2A). Furthermore, CCK-8 assay showed that the gure 2C). Furthermore, transwell assay showed proliferation of NPC cells was suppressed after that the invasion of NPC cells was inhibited after SNHG7 knockdown (Figure 2B). SNHG7 knockdown (Figure 2D).

Figure 2. Knockdown of SNHG7 inhibited NPC cell proliferation, migration and invasion. A, SNHG7 expression in NPC cells transfected with empty vector (EV) or SNHG7 shRNA (sh-SNHG7) was detected by RT-qPCR. GAPDH was used as an internal control. B, CCK-8 assay showed that knockdown of SNHG7 significantly repressed proliferation in 5-8F NPC cells. C, Wound-healing assay showed that the invasive length of cells in SNHG7 lentivirus group significantly decreased compared with empty control group in 5-8F NPC cells (magnification: 40×). D, Transwell assay showed that knockdown of SNHG7 significantlyRETRACTED repressed invasion in 5-8F NPC cells (magnification: 40×). The results represent the average of three independent experiments (mean ± standard error of the mean). *p<0.05, as compared with the control cells.

6189 L. Wang, T. Xu, X. Cui, M. Han, L.-H. Zhou, Z.-X. Wei, Z.-J. Xu, Y. Jiang

SNHG7 Promoted NPC Tumorigenesis SNHG7 Knockdown Inhibited Tumor via ROCK1 Formation and Metastasis in Vivo RT-qPCR results demonstrated that the mRNA In vivo ability of SNHG7 in tumor formation expression of ROCK1 was downregulated in NPC and metastasis of NPC was detected. The tumor cells transfected with sh-SNHG7 (Figure 3A). size in sh-SNHG7 group was smaller compared Western blot analysis results further verified that with that in EV group (Figure 4A). The weight of the protein expression of ROCK1 was downregu- dissected tumors in sh-SNHG7 group was smaller lated in NPC cells transfected with sh-SNHG7 as compared with that in EV group (Figure 4B). The well (Figure 3B). Subsequently, we further explo- number of metastatic nodules in the lung from red the interaction between SNHG7 and ROCK1. the sh-SNHG7 group was significantly reduced As a result, ROCK1 was upregulated in NPC tis- compared to EV group (Figure 4C). Moreover, sues compared with that in adjacent tissues (Figu- SNHG7 expression in dissected tumor tissues re 3C). Linear correlation analysis showed a posi- was detected by RT-qPCR. The results showed tive correlation between ROCK1 expression and that SNHG7 was lowly expressed in sh-SNHG7 SNHG7 expression in NPC tissues (Figure 3D). group compared with that in EV group (Figure

Figure 3. Interaction between ROCK1 and SNHG7 in NPC. A, The RNA level of ROCK1 in sh-SNHG7 group significantly decreased compared with EV group in 5-8F cells. B, Protein expression of ROCK1 was downregulated after knockdown of SNHG7 in 5-8F cells. C, ROCK1 was significantly upregulated in NPC tissues compared with adjacent tissues. D, The linear correlationRETRACTED between the expression levels of ROCK1 and SNHG7 in NPC tissues. The results represent the average of three independent experiments Data are presented as the mean ± standard error of the mean. *p<0.05.

6190 LncRNA SNHG7 inhibits the progression of nasopharyngeal carcinoma

Figure 4. Knockdown of SNHG7 inhibited tumor formation and metastasis of NPC in vivo. A, The tumor size in sh-SNHG7 group was smaller compared with EV group. B, The weight of dissected tumors in sh-SNHG7 group was smaller compared with EV group. C, The number of metastatic nodules in the lung from the sh-SNHG7 group was significantly reduced compared to EV group. D, SNHG7 in those dissected tumors was lowly expressed in sh-SNHG7 group compared with EV group. The results represent the average of three independent experiments (mean ± standard error of the mean). *p<0.05, as compared with the control cells.

4D). Above results suggested that SNHG7 could potential NPC biomarker11. Small nucleolar RNA induce tumor formation and metastasis of NPC host gene 7 (SNHG7) is an oncogene located on in vivo. chromosome 9q34.3, which is 2176 bp in length. Numerous researches have revealed that SNHG7 promotes cell proliferation, invasion and migra- Discussion tion in many cancers12. For example, SNHG7 fa- cilitates the epithelial-to-mesenchymal transition Evidence suggested that lncRNAs are crucial and tumor proliferation in osteosarcoma by regu- regulators in carcinogenesis of NPC. For instan- lating miR-34a13. Knockdown of SNHG7 signi- ce, upregulated expression of lncRNA AFAP1- ficantly inhibits cell proliferation and migration AS1 promotes the progression of NPC and is in glioblastoma through inhibiting miR-509514. negatively related to the poor prognosis of NPC SNHG7 promotes the progression of non-small patients8. LncRNA ROR enhances cell prolife- cell lung cancer by enhancing miR-193b level ration, migration, and chemoresistance in NPC and reducing FAIM2 expression15. In addition, via suppressing p53 signaling pathway9. Throu- SNHG7 is upregulated in colorectal cancer and gh targeting miR-214, lncRNA LINC0086 serves negatively related to its prognosis by regulating as a tumor suppressor in NPC and may provide PI3K/Akt/mTOR pathway16. In the present study, a potential treatment target for NPC10. LncRNA SNHG7 was found to be upregulated in both NPC FOXCUTRETRACTED facilitates cell proliferation and migra- tissues and cells. Furthermore, SNHG7 knock- tion in NPC via targeting FOXC1, which may be a down attenuated growth, migration and invasion

6191 L. Wang, T. Xu, X. Cui, M. Han, L.-H. Zhou, Z.-X. Wei, Z.-J. Xu, Y. Jiang

of NPC cells. In addition, knockdown of SNHG7 and FOXO4 and the local recurrence and me- inhibited tumor formation and metastasis of NPC tastasis of nasopharyngeal carcinoma after in- in vivo. These data indicated that SNHG7 functio- tensive radiotherapy. J BUON 2018; 23: 1671- ned as an oncogene and promoted the tumorige- 1678. nesis of NPC. Rho-associated kinase 1 (ROCK1), 3) Kamran SC, Riaz N, Lee N. Nasopharyngeal carci- a protein serine/threonine kinase, has been repor- noma. Surg Oncol Clin N Am 2015; 24: 547-561. Fritah S, Niclou SP, Azuaje F. ted to participate in a variety of biological and 4) Databases for ln- cRNAs: a comparative evaluation of emerging pathological processes, including cell motility, tools. RNA 2014; 20: 1655-1665. tumor metastasis and epithelial-to-mesenchymal 5) Jia Z, Peng J, Yang Z, Chen J, Liu L, Luo D, He P. 17 transition (EMT) . For instance, Mst1 regulates Long non-coding RNA TP73AS1 promotes col- mitochondrial injury-induced cell apoptosis in orectal cancer proliferation by acting as a ceRNA NSCLC by ROCK1/Factin pathway18. Silencing for miR103 to regulate PTEN expression. Gene of URG11 represses the proliferation and EMT in 2019; 685: 222-229. benign prostatic hyperplasia cells through RhoA/ 6) Chen X, Li J, Li CL, Lu X. Long non-coding 19 RNA ZFAS1 promotes nasopharyngeal carcino- ROCK1 pathway . LncRNA LOC441178 inhibi- ma through activation of Wnt/beta-catenin path- ts cell invasion and migration in oral squamous way. Eur Rev Med Pharmacol Sci 2018; 22: 3423- carcinoma via targeting ROCK120. In our study, 3429. ROCK1 was downregulated after SNHG7 knock- 7) Chen J, Huang X, Wang W, Xie H, Li J, Hu Z, Zheng down in vitro. Moreover, ROCK1 was remarkably Z, Li H, Teng L. LncRNA CDKN2BAS predicts poor upregulated in NPC samples compared with that prognosis in patients with hepatocellular carcino- in adjacent tissues. A positive correlation was di- ma and promotes metastasis via the miR-153- 5p/ARHGAP18 signaling axis. Aging (Albany NY) scovered between ROCK1 and SNHG7 expres- 2018; 10: 3371-3381. sions in NPC tissues. It is revealed that SNHG7 8) Bo H, Gong Z, Zhang W, Li X, Zeng Y, Liao Q, Chen may realize its function via regulating ROCK1. P, Shi L, Lian Y, Jing Y, Tang K, Li Z, Zhou Y, Zhou M, Xiang B, Li X, Yang J, Xiong W, Li G, Zeng Z. Up- regulated long non-coding RNA AFAP1-AS1 ex- Conclusions pression is associated with progression and poor prognosis of nasopharyngeal carcinoma. Onco- target 2015; 6: 20404-20418. LncRNA SNHG7 promotes NPC carcinogene- 9) Li L, Gu M, You B, Shi S, Shan Y, Bao L, You Y. sis via regulating ROCK1, which can be served as Long non-coding RNA ROR promotes prolifer- a promising marker for NPC. ation, migration and chemoresistance of naso- pharyngeal carcinoma. Cancer Sci 2016; 107: 1215-1222. Conflict of Interest 10) Guo J, Ma J, Zhao G, Li G, Fu Y, Luo Y, Gui R. Long The Authors declare that they have no conflict of interests. noncoding RNA LINC0086 functions as a tumor suppressor in nasopharyngeal carcinoma by tar- geting miR-214. Oncol Res 2017; 25: 1189-1197. Xu YZ, Chen FF, Zhang Y, Zhao QF, Guan XL, Acknowledgements 11) Wang HY, Li A, Lv X, Song SS, Zhou Y, Li XJ. The The study was granted by National Science Foundation long noncoding RNA FOXCUT promotes prolif- of China (No.81770978); The Key Research and Develop- eration and migration by targeting FOXC1 in na- ment Program of Shandong Province (2018GSF118012); sopharyngeal carcinoma. Tumour Biol 2017; 39: The Shandong Medical and Health Science and Technolo- 1393383610. gy Development Plan (2016WS0268) and China Postdoctor- al Science Foundation (20110491558). 12) Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimu- ra K, Makita H, Sekine M, Obayashi M, Nishi T, Shiba- hara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai References Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Ya- suda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara Yi M, Cai J, Li J, Chen S, Zeng Z, Peng Q, Ban Y, 1) M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa Zhou Y, Li X, Xiong W, Li G, Xiang B . Rediscovery E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, of NF-kappaB signaling in nasopharyngeal carci- Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Ya- noma: how genetic defects of NF-kappaB path- mashita H, Murakawa K, Fujimori K, Tanai H, Kimata way interplay with EBV in driving oncogenesis? J M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Cell Physiol 2018; 233: 5537-5549. Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano Liu B, Tan Z, Jiang Y, Chen Y, Chen Y, Ling K 2) RETRACTED. J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Correlation between the expression of miR150 Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Ar-

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