lncRNA ST3GAL6‑AS1 promotes invasion by inhibiting hnRNPA2B1‑mediated ST3GAL6 expression in multiple myeloma

Shen,Ying; Feng,Yuandong; Li,Fangmei; Jia,Yachun; Peng,Yue; Zhao,Wanhong; Hu,Jinsong; He,Aili

doi:10.3892/ijo.2021.5185

lncRNA ST3GAL6‑AS1 promotes invasion by inhibiting hnRNPA2B1‑mediated ST3GAL6 expression in multiple myeloma

Authors:
- Ying Shen
- Yuandong Feng
- Fangmei Li
- Yachun Jia
- Yue Peng
- Wanhong Zhao
- Jinsong Hu
- Aili He
View Affiliations

Affiliations: Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi 710001, P.R. China
Published online on: February 8, 2021 https://doi.org/10.3892/ijo.2021.5185
Article Number: 5

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Multiple myeloma (MM) is an incurable disease caused by the infiltration of malignant plasma B cells into bone marrow, whose pathogenesis remains largely unknown. Long non‑coding RNAs (lncRNAs) have emerged as important factors in pathogenesis. Our previous study validated that lncRNA ST3 β‑galactoside α‑2,3‑sialyltransferase 6 antisense RNA 1 (ST3GAL6‑AS1) was upregulated markedly in MM. Therefore, the aim of the study was to investigate the molecular mechanisms of ST3GAL6‑AS1 in MM cells. ST3GAL6‑AS1 expression levels in MM cells was detected using reverse transcription‑quantitative PCR. ST3GAL6‑AS1 antisense oligonucleotides and small interfering RNAs were transfected into MM cells to downregulate expression. In vitro assays were performed to investigate the functional role of ST3GAL6‑AS1 in MM cells. RNA pull‑down, RNA immunoprecipitation and comprehensive identification of RNA‑binding proteins using mass spectrometry assays were used to determine the mechanism of ST3GAL6‑AS1‑mediated regulation of underlying targets. It was reported that knockdown of ST3GAL6‑AS1 suppressed the adhesion, migration and invasion ability of MM cells in vitro. Expression of ST3GAL6 was significantly reduced when ST3GAL6‑AS1 was knock downed in MM cells. Moreover, mechanistic investigation showed that ST3GAL6‑AS1 could suppress ST3GAL6 mRNA degradation via interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). The present results suggested that upregulated lncRNA ST3GAL6‑AS1 promotes adhesion and invasion of MM cells by binding with hnRNPA2B1 to regulate ST3GAL6 expression.

View Figures

View References

1	Rajkumar SV: Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 95:548–567. 2020. View Article : Google Scholar : PubMed/NCBI
2	Nobili L, Ronchetti D, Agnelli L, Taiana E, Vinci C and Neri A: Long non-coding RNAs in multiple myeloma. Genes (Basel). 9:692018. View Article : Google Scholar
3	Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, Gay F and Anderson KC: Multiple myeloma. Nat Rev Dis Primers. 3:170462017. View Article : Google Scholar
4	Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, Abdelalim A, Abdoli A, Abdollahpour I, Abdulle AS, et al Global Burden of Disease Cancer Collaboration: Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 5:1749–1768. 2019. View Article : Google Scholar : PubMed/NCBI
5	Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M and Dimopoulos MA: Pathogenesis of bone disease in multiple myeloma: From bench to bedside. Blood Cancer J. 8:72018. View Article : Google Scholar : PubMed/NCBI
6	Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, Giralt S, Mateos MV, Leleu X and Anderson KC: Management of relapsed and refractory multiple myeloma: Novel agents, antibodies, immunotherapies and beyond. Leukemia. 32:252–262. 2018. View Article : Google Scholar :
7	Soekojo CY, Ooi M, de Mel S and Chng WJ: Immunotherapy in multiple myeloma. Cells. 9:92020. View Article : Google Scholar
8	Robak P, Drozdz I, Szemraj J and Robak T: Drug resistance in multiple myeloma. Cancer Treat Rev. 70:199–208. 2018. View Article : Google Scholar : PubMed/NCBI
9	Amodio N, Stamato MA, Juli G, Morelli E, Fulciniti M, Manzoni M, Taiana E, Agnelli L, Cantafio ME, Romeo E, et al: Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. Leukemia. 32:1948–1957. 2018. View Article : Google Scholar : PubMed/NCBI
10	Zhou M, Zhao H, Wang Z, Cheng L, Yang L, Shi H, Yang H and Sun J: Identification and validation of potential prognostic lncRNA biomarkers for predicting survival in patients with multiple myeloma. J Exp Clin Cancer Res. 34:1022015. View Article : Google Scholar : PubMed/NCBI
11	Kopp F and Mendell JT: Functional classification and experi- mental dissection of long noncoding RNAs. Cell. 172:393–407. 2018. View Article : Google Scholar : PubMed/NCBI
12	Shen Y, Feng Y, Chen H, Huang L, Wang F, Bai J, Yang Y, Wang J, Zhao W, Jia Y, et al: Focusing on long non-coding RNA dysregulation in newly diagnosed multiple myeloma. Life Sci. 196:133–142. 2018. View Article : Google Scholar : PubMed/NCBI
13	Glavey SV, Manier S, Natoni A, Sacco A, Moschetta M, Reagan MR, Murillo LS, Sahin I, Wu P, Mishima Y, et al: The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma. Blood. 124:1765–1776. 2014. View Article : Google Scholar : PubMed/NCBI
14	Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, et al: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15:e538–e548. 2014. View Article : Google Scholar : PubMed/NCBI
15	Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Bladé J, Mateos MV, et al: International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 17:e328–e346. 2016. View Article : Google Scholar : PubMed/NCBI
16	Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, Dispenzieri A, Fonseca R, Sher T, Kyle RA, et al Mayo Clinic: Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 88:360–376. 2013. View Article : Google Scholar : PubMed/NCBI
17	Grammatikakis I, Zhang P, Panda AC, Kim J, Maudsley S, Abdelmohsen K, Yang X, Martindale JL, Motiño O, Hutchison ER, et al: Alternative splicing of neuronal differentiation factor TRF2 regulated by HNRNPH1/H2. Cell Rep. 15:926–934. 2016. View Article : Google Scholar : PubMed/NCBI
18	Peng Y, Li F, Zhang P, Wang X, Shen Y, Feng Y, Jia Y, Zhang R, Hu J and He A: IGF-1 promotes multiple myeloma progression through PI3K/Akt-mediated epithelial-mesenchymal transition. Life Sci. 249:1175032020. View Article : Google Scholar
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
20	Schmitz SU, Grote P and Herrmann BG: Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci. 73:2491–2509. 2016. View Article : Google Scholar : PubMed/NCBI
21	Cho SF, Chang YC, Chang CS, Lin SF, Liu YC, Hsiao HH, Chang JG and Liu TC: MALAT1 long non-coding RNA is overexpressed in multiple myeloma and may serve as a marker to predict disease progression. BMC Cancer. 14:8092014. View Article : Google Scholar : PubMed/NCBI
22	Handa H, Kuroda Y, Kimura K, Masuda Y, Hattori H, Alkebsi L, Matsumoto M, Kasamatsu T, Kobayashi N, Tahara KI, et al: Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma. Br J Haematol. 179:449–460. 2017. View Article : Google Scholar : PubMed/NCBI
23	Hu Y, Lin J, Fang H, Fang J, Li C, Chen W, Liu S, Ondrejka S, Gong Z, Reu F, et al: Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia. 32:2250–2262. 2018. View Article : Google Scholar : PubMed/NCBI
24	Li B, Chen P, Qu J, Shi L and Zhuang W, Fu J, Li J, Zhang X, Sun Y and Zhuang W: Activation of LTBP3 gene by a long noncoding RNA (lncRNA) MALAT1 transcript in mesenchymal stem cells from multiple myeloma. J Biol Chem. 289:29365–29375. 2014. View Article : Google Scholar : PubMed/NCBI
25	Liu H, Wang H, Wu B, Yao K, Liao A, Miao M, Li Y and Yang W: Down-regulation of long non-coding RNA MALAT1 by RNA interference inhibits proliferation and induces apoptosis in multiple myeloma. Clin Exp Pharmacol Physiol. 44:1032–1041. 2017. View Article : Google Scholar : PubMed/NCBI
26	Sedlarikova L, Gromesova B, Kubaczkova V, Radova L, Filipova J, Jarkovsky J, Brozova L, Velichova R, Almasi M, Penka M, et al: Deregulated expression of long non-coding RNA UCA1 in multiple myeloma. Eur J Haematol. 99:223–33. 2017. View Article : Google Scholar : PubMed/NCBI
27	Wu Y and Wang H: LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR-193a/MCL1 pathway. J Biochem Mol Toxicol. 32:e220082018. View Article : Google Scholar
28	Hu J, Shan Y, Ma J, Pan Y, Zhou H, Jiang L and Jia L: LncRNA ST3Gal6-AS1/ST3Gal6 axis mediates colorectal cancer progression by regulating α-2,3 sialylation via PI3K/Akt signaling. Int J Cancer. 145:450–460. 2019. View Article : Google Scholar : PubMed/NCBI
29	Gan L, Lv L and Liao S: Long non coding RNA H19 regulates cell growth and metastasis via the miR 22 3p/Snail1 axis in gastric cancer. Int J Oncol. 54:2157–2168. 2019.PubMed/NCBI
30	Luo M, Li Z, Wang W, Zeng Y, Liu Z and Qiu J: Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 333:213–221. 2013. View Article : Google Scholar : PubMed/NCBI
31	Chen SW, Zhu J, Ma J, Zhang JL, Zuo S, Chen GW, Wang X, Pan YS, Liu YC and Wang PY: Overexpression of long non-coding RNA H19 is associated with unfavorable prognosis in patients with colorectal cancer and increased proliferation and migration in colon cancer cells. Oncol Lett. 14:2446–2452. 2017. View Article : Google Scholar : PubMed/NCBI
32	Zhu M, Chen Q, Liu X, Sun Q, Zhao X, Deng R, Wang Y, Huang J, Xu M, Yan J, et al: lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI. FEBS J. 281:3766–3775. 2014. View Article : Google Scholar : PubMed/NCBI
33	Ding K, Liao Y, Gong D, Zhao X and Ji W: Effect of long non-coding RNA H19 on oxidative stress and chemotherapy resistance of CD133⁺ cancer stem cells via the MAPK/ERK signaling pathway in hepatocellular carcinoma. Biochem Biophys Res Commun. 502:194–201. 2018. View Article : Google Scholar : PubMed/NCBI
34	Tsang WP and Kwok TT: Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene. 26:4877–4881. 2007. View Article : Google Scholar : PubMed/NCBI
35	Teppa RE, Petit D, Plechakova O, Cogez V and Harduin-Lepers A: Phylogenetic-derived insights into the evolution of sialylation in eukaryotes: Comprehensive analysis of vertebrate β-galactoside α2,3/6-sialyltransferases (ST3Gal and ST6Gal). Int J Mol Sci. 17:172016. View Article : Google Scholar
36	Sun M, Zhao X, Liang L, Pan X, Lv H and Zhao Y: Sialyltransferase ST3GAL6 mediates the effect of microRNA-26a on cell growth, migration, and invasion in hepatocellular carcinoma through the protein kinase B/mammalian target of rapamycin pathway. Cancer Sci. 108:267–276. 2017. View Article : Google Scholar :
37	Shi J, Li YM and Fang XD: The mechanism and clinical significance of long noncoding RNA-mediated gene expression via nuclear architecture. Yi Chuan. 39:189–199. 2017.PubMed/NCBI
38	Jandura A and Krause HM: The new RNA world: Growing evidence for long noncoding RNA functionality. Trends Genet. 33:665–676. 2017. View Article : Google Scholar : PubMed/NCBI
39	Alvarez-Dominguez JR and Lodish HF: Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis. Blood. 130:1965–1975. 2017. View Article : Google Scholar : PubMed/NCBI
40	Geuens T, Bouhy D and Timmerman V: The hnRNP family: Insights into their role in health and disease. Hum Genet. 135:851–867. 2016. View Article : Google Scholar : PubMed/NCBI
41	Ford LP, Wright WE and Shay JW: A model for heterogeneous nuclear ribonucleoproteins in telomere and telomerase regulation. Oncogene. 21:580–583. 2002. View Article : Google Scholar : PubMed/NCBI
42	Shishkin SS, Kovalev LI, Pashintseva NV, Kovaleva MA and Lisitskaya K: Heterogeneous nuclear ribonucleoproteins involved in the functioning of telomeres in malignant cells. Int J Mol Sci. 20:202019. View Article : Google Scholar
43	He Y and Smith R: Nuclear functions of heterogeneous nuclear ribonucleoproteins A/B. Cell Mol Life Sci. 66:1239–1256. 2009. View Article : Google Scholar
44	Wang L, Wen M and Cao X: Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses. Science. 365:3652019. View Article : Google Scholar
45	Qin G, Tu X, Li H, Cao P, Chen X, Song J, Han H, Li Y, Guo B, Yang L, et al: Long Noncoding RNA p53-stabilizing and activating RNA promotes p53 signaling by inhibiting heterogeneous nuclear ribonucleoprotein K deSUMOylation and suppresses hepatocellular carcinoma. Hepatology. 71:112–129. 2020. View Article : Google Scholar
46	Lan X, Yan J, Ren J, Zhong B, Li J, Yue L, Liu L, Yi J, Sun Q, Yang X, et al: A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology. 64:58–72. 2016. View Article : Google Scholar
47	Chen C, Luo Y, He W, Zhao Y, Kong Y, Liu H, Zhong G, Li Y, Li J, Huang J, et al: Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer. J Clin Invest. 130:404–421. 2019. View Article : Google Scholar : PubMed/NCBI