Abstract
Pancreatic cancer is a deadly cancer. More and more long noncoding RNAs (lncRNAs) have received confirmation to be dysregulated in tumors and exert the regulatory function. Studies have suggested that lncRNA insulin-like growth factor 2 antisense RNA (IGF2-AS) participates in the development of some cancers. Thus, we attempted to clarify its function in pancreatic cancer. Reverse-transcription quantitative polymerase chain reaction was applied for testing IGF2-AS expression in pancreatic cancer cells. Colony formation and Transwell wound experiments were applied for determining cell proliferative, migratory, and invasive capabilities. The alteration of epithelial-mesenchymal transition (EMT)-related gene level was tested via western blot. The mice model was established for measuring the tumor growth and metastasis. RIP validated the interaction of RNAs. IGF2-AS displays high expression in pancreatic cancer cells. IGF2-AS depletion repressed PC cell proliferative, migratory, invasive capabilities, and EMT process. Furthermore, pancreatic cancer tumor growth and metastasis were also inhibited by IGF2-AS depletion. Additionally, IGF2-AS positively regulated IGF2 level via recruiting HNRNPC. IGF2 overexpression counteracted the functions of IGF2-AS deficiency on pancreatic cancer cell behaviors. Moreover, IGF2R deletion was found to inhibit the positive effect of IGF2 on pancreatic cancer progression. IGF2-AS potentiates pancreatic cancer cell proliferation, tumor growth, and metastasis by recruiting HNRNPC via the IGF2-IGF2R regulatory pathway. These discoveries might offer a novel insight for treatment of PC, which may facilitate targeted therapies of PC in clinical practice.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Original data can be obtained from the corresponding author under reasonable requests.
References
Bhan A, Soleimani M, Mandal SS (2017) Long noncoding RNA and cancer: a new paradigm. Cancer Res 77:3965–3981. https://doi.org/10.1158/0008-5472.Can-16-2634
Chan JJ, Tay Y (2018) Noncoding RNA: RNA regulatory networks in cancer. Int J Mol Sci 19(5):1310. https://doi.org/10.3390/ijms19051310
Chen C, Ding P, Yan W, Wang Z, Lan Y, Yan X, Li T, Han J (2023) Pharmacological roles of lncRNAs in diabetic retinopathy with a focus on oxidative stress and inflammation. Biochem Pharmacol 214:115643. https://doi.org/10.1016/j.bcp.2023.115643
Chen W, Wang F, Zhang J, Li C, Hong L (2022) LINC01087 indicates a poor prognosis of glioma patients with preoperative MRI. Funct Integr Genomics 22:55–64. https://doi.org/10.1007/s10142-021-00812-w
Cheng F, Wang L, Yi S (2022) Long non-coding RNA SNHG1/microRNA-195-5p/Yes-associated protein axis affects the proliferation and metastasis of gastric cancer via the Hippo signaling pathway. Funct Integr Genomics 22:1043–1055. https://doi.org/10.1007/s10142-022-00876-2
Dong Y, Li J, Han F, Chen H, Zhao X, Qin Q, Shi R, Liu J (2015) High IGF2 expression is associated with poor clinical outcome in human ovarian cancer. Oncol Rep 34:936–942. https://doi.org/10.3892/or.2015.4048
Feng Y, Yang Y, Fan C, Di S, Hu W, Jiang S, Li T, Ma Z, Chao D, Feng X, Xin Z, Pang S, Li X, Yan X (2016) Pterostilbene inhibits the growth of human esophageal cancer cells by regulating endoplasmic reticulum stress. Cell Physiol Biochem 38:1226–1244. https://doi.org/10.1159/000443071
Gao W, Gu Y, Li Z, Cai H, Peng Q, Tu M, Kondo Y, Shinjo K, Zhu Y, Zhang J, Sekido Y, Han B, Qian Z, Miao Y (2015) miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene 34:1629–1640. https://doi.org/10.1038/onc.2014.101
Georg J, Hess WR (2018) Widespread antisense transcription in prokaryotes. Microbiol Spectr 6. https://doi.org/10.1128/microbiolspec.RWR-0029-2018
Han Q, Li J, Xiong J, Song Z (2020) Long noncoding RNA LINC00514 accelerates pancreatic cancer progression by acting as a ceRNA of miR-28-5p to upregulate Rap1b expression. J Exp Clin Cancer Res 39:151. https://doi.org/10.1186/s13046-020-01660-5
Harris LK, Westwood M (2012) Biology and significance of signalling pathways activated by IGF-II. Growth Factors 30:1–12. https://doi.org/10.3109/08977194.2011.640325
Hu X, Wu J, Xu J (2023) UCA1 executes an oncogenic role in pancreatic cancer by regulating miR-582-5p/BRCC3. Front Oncol 13:1133200. https://doi.org/10.3389/fonc.2023.1133200
Huang GS, Brouwer-Visser J, Ramirez MJ, Kim CH, Hebert TM, Lin J, Arias-Pulido H, Qualls CR, Prossnitz ER, Goldberg GL, Smith HO, Horwitz SB (2010) Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin Cancer Res 16:2999–3010. https://doi.org/10.1158/1078-0432.Ccr-09-3233
Huang H, Li X, Zhang X, Li Z, Han D, Gao W, Liu L, Peng C, Zhu H, Yu X (2022) DSCR9/miR-21-5p axis inhibits pancreatic cancer proliferation and resistance to gemcitabine via BTG2 signaling. Acta Biochim Biophys Sin 54:1775–1788. https://doi.org/10.3724/abbs.2022194
Jin X, Feng J, Cheng X (2022) LncRNA IGF2-AS promotes endometriosis progression through targeting miR-370-3p/IGF2 axis and activating PI3K/AKT/mTOR signaling pathway. J Assist Reprod Genet 39:2699–2710. https://doi.org/10.1007/s10815-022-02638-2
Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172:393–407. https://doi.org/10.1016/j.cell.2018.01.011
Lee EK, Kim HH, Kuwano Y, Abdelmohsen K, Srikantan S, Subaran SS, Gleichmann M, Mughal MR, Martindale JL, Yang X, Worley PF, Mattson MP, Gorospe M (2010) hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol 17:732–739. https://doi.org/10.1038/nsmb.1815
Li S, Dong R, Kang Z, Li H, Wu X, Li T (2023a) Exosomes: another intercellular lipometabolic communication mediators in digestive system neoplasms? Cytokine Growth Factor Rev 73:93–100. https://doi.org/10.1016/j.cytogfr.2023.06.005
Li S, Jiang F, Chen F, Deng Y, Huang H (2023b) Silencing long noncoding RNA LINC01133 suppresses pancreatic cancer through regulation of microRNA-1299-dependent IGF2BP3.e23534. https://doi.org/10.1002/jbt.23534
Li T, Yang Z (2018) Melatonin: does it have utility in the treatment of haematological neoplasms? Br J Pharmacol 175:3251–3262. https://doi.org/10.1111/bph.13966
Li Y, Zhang Z, Yang Y, Ma J (2020) Long Noncoding RNA HOX Transcript antisense RNA gene rs17720428 single nucleotide polymorphism is associated with gastric cancer risk and prognosis. Genet Test Mol Biomark 24:38–46. https://doi.org/10.1089/gtmb.2019.0140
Liu SB, Zhou LB, Wang HF, Li G, Xie QP, Hu B (2020) Loss of IGF2R indicates a poor prognosis and promotes cell proliferation and tumorigenesis in bladder cancer via AKT signaling pathway. Neoplasma 67:129–136. https://doi.org/10.4149/neo_2019_190206N108
Livingstone C (2013) IGF2 and cancer. Endocr Relat Cancer 20:R321–R339. https://doi.org/10.1530/erc-13-0231
Ma Z, Fan C, Yang Y, Di S, Hu W, Li T, Zhu Y, Han J, Xin Z, Wu G, Zhao J, Li X, Yan X (2016) Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation. Sci Rep 6:35196. https://doi.org/10.1038/srep35196
Martinez-Quetglas I, Pinyol R, Dauch D, Torrecilla S, Tovar V, Moeini A, Alsinet C, Portela A, Rodriguez-Carunchio L, Solé M, Lujambio A, Villanueva A, Thung S, Esteller M, Zender L, Llovet JM (2016) IGF2 is up-regulated by epigenetic mechanisms in hepatocellular carcinomas and is an actionable oncogene product in experimental models. Gastroenterology 151:1192–1205. https://doi.org/10.1053/j.gastro.2016.09.001
Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159. https://doi.org/10.1038/nrg2521
Ou JM, Lian WS, Qiu MK, Dai YX, Dong Q, Shen J, Dong P, Wang XF, Liu YB, Quan ZW, Fei ZW (2014) Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo. Int J Oncol 45:1241–1249. https://doi.org/10.3892/ijo.2014.2512
Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29:212–226. https://doi.org/10.1016/j.tcb.2018.12.001
Reymond N, d'Água BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870. https://doi.org/10.1038/nrc3628
Schagdarsurengin U, Lammert A, Schunk N, Sheridan D, Gattenloehner S, Steger K, Wagenlehner F, Dansranjavin T (2017) Impairment of IGF2 gene expression in prostate cancer is triggered by epigenetic dysregulation of IGF2-DMR0 and its interaction with KLF4. Cell Commun Signal 15:40. https://doi.org/10.1186/s12964-017-0197-7
Sferruzzi-Perri AN, Sandovici I, Constancia M, Fowden AL (2017) Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth. J Physiol 595:5057–5093. https://doi.org/10.1113/jp273330
Shen XM, Han S, Liu N, Xu HQ, Yan CX, Yu CJ (2021) LINC00887 aggravates the malignant progression of glioma via upregulating CCND1. Eur Rev Med Pharmacol Sci 25:1928–1935. https://doi.org/10.26355/eurrev_202102_25091
Shi F, Li T, Liu Z, Qu K, Shi C, Li Y, Qin Q, Cheng L, Jin X, Yu T, Di W, Que J, Xia H, She J (2018) FOXO1: another avenue for treating digestive malignancy? Semin Cancer Biol 50:124–131. https://doi.org/10.1016/j.semcancer.2017.09.009
St Laurent G, Wahlestedt C, Kapranov P (2015) The Landscape of long noncoding RNA classification. Trends Genet 31:239–251. https://doi.org/10.1016/j.tig.2015.03.007
Stylianopoulou F, Efstratiadis A, Herbert J, Pintar J (1988) Pattern of the insulin-like growth factor II gene expression during rat embryogenesis. Development 103:497–506. https://doi.org/10.1242/dev.103.3.497
Sulidankazha C, Alidake (2023) LncRNA MBNL1-AS1 suppresses cell proliferation and metastasis of pancreatic adenocarcinoma through targeting carcinogenic miR-301b-3p. Genet Res 2023:6785005. https://doi.org/10.1155/2023/6785005
Sun M, Liu X, Xia L, Chen Y, Kuang L, Gu X, Li T (2021) A nine-lncRNA signature predicts distant relapse-free survival of HER2-negative breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. Biochem Pharmacol 189:114285. https://doi.org/10.1016/j.bcp.2020.114285
Tominaga K, Shimamura T, Kimura N, Murayama T, Matsubara D, Kanauchi H, Niida A, Shimizu S, Nishioka K, Tsuji EI, Yano M, Sugano S, Shimono Y, Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa T et al (2017) Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. Oncogene 36:1276–1286. https://doi.org/10.1038/onc.2016.293
Velusamy T, Shetty P, Bhandary YP, Liu MC, Shetty S (2008) Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C. Biochemistry 47:6508–6517. https://doi.org/10.1021/bi702338y
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378:607–620. https://doi.org/10.1016/s0140-6736(10)62307-0
Vu TH, Jirtle RL, Hoffman AR (2006) Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene. Cytogenet Genome Res 113:202–208. https://doi.org/10.1159/000090833
Wang S, Xia L, Zhang B, Zhang H, Lan F (2022a) Downregulated long intergenic non-coding RNA 00,174 represses malignant biological behaviors of lung cancer cells by regulating microRNA-584-3p/ribosomal protein S24 axis. Funct Integr Genomics 22:643–653. https://doi.org/10.1007/s10142-022-00855-7
Wang W, Dong ML, Zhang W, Liu T (2021a) Long noncoding LUCAT1 promotes cisplatin resistance of non-small cell lung cancer by promoting IGF-2. Eur Rev Med Pharmacol Sci 25:–567. https://doi.org/10.26355/eurrev_202101_24593
Wang Y, Li T, Yang Q, Feng B, Xiang Y, Lv Z, Weng X (2021b) LncRNA THUMPD3-AS1 enhances the proliferation and inflammatory response of chondrocytes in osteoarthritis. International immunopharmacology 100:108138. https://doi.org/10.1016/j.intimp.2021.108138
Wang Y, Liu F, Chen L, Fang C, Li S, Yuan S, Qian X, Yin Y, Yu B, Fu B, Zhang X, Li Y (2022b) Neutrophil Extracellular Traps (NETs) Promote non-small cell lung cancer metastasis by suppressing lncRNA MIR503HG to activate the NF-κB/NLRP3 inflammasome pathway. Front Immunol 13:867516. https://doi.org/10.3389/fimmu.2022.867516
Wise TL, Pravtcheva DD (2006) Delayed onset of Igf2-induced mammary tumors in Igf2r transgenic mice. Cancer Res 66:1327–1336. https://doi.org/10.1158/0008-5472.Can-05-3107
Wu W, Gao H, Li X, Zhu Y, Peng S, Yu J, Zhan G, Wang J, Liu N, Guo X (2019) LncRNA TPT1-AS1 promotes tumorigenesis and metastasis in epithelial ovarian cancer by inducing TPT1 expression. Cancer Sci 110:1587–1598. https://doi.org/10.1111/cas.14009
Xie W, Chu M, Song G, Zuo Z, Han Z, Chen C, Li Y, Wang ZW (2022) Emerging roles of long noncoding RNAs in chemoresistance of pancreatic cancer. Semin Cancer Biol 83:303–318. https://doi.org/10.1016/j.semcancer.2020.11.004
Xu J, Wang J, He Z, Chen P, Jiang X, Chen Y, Liu X, Jiang J (2021) LncRNA CERS6-AS1 promotes proliferation and metastasis through the upregulation of YWHAG and activation of ERK signaling in pancreatic cancer. Cell Death Dis 12:648. https://doi.org/10.1038/s41419-021-03921-3
Xu WW, Li B, Guan XY, Chung SK, Wang Y, Yip YL, Law SY, Chan KT, Lee NP, Chan KW, Xu LY, Li EM, Tsao SW, He QY, Cheung AL (2017) Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression. Nat Commun 8:14399. https://doi.org/10.1038/ncomms14399
Yan B, Ren Z, Sun J, Ding C, Yang D (2020) IGF2-AS knockdown inhibits glycolysis and accelerates apoptosis of gastric cancer cells through targeting miR-195/CREB1 axis. Biomed Pharmacother 130:110600. https://doi.org/10.1016/j.biopha.2020.110600
Yan LR, Ding HX, Shen SX, Lu XD, Yuan Y, Xu Q (2021) Pepsinogen C expression-related lncRNA/circRNA/mRNA profile and its co-mediated ceRNA network in gastric cancer. Funct Integr Genomics 21:605–618. https://doi.org/10.1007/s10142-021-00803-x
Yan Z, Li J, Guo J, He R, Xing J (2022) LncRNA XIST sponges microRNA-448 to promote malignant behaviors of colorectal cancer cells via regulating GRHL2. Funct Integr Genomics 22:977–988. https://doi.org/10.1007/s10142-022-00873-5
Yao J, Gao R, Luo M, Li D, Guo L, Yu Z, Xiong F, Wei C, Wu B, Xu Z, Zhang D (2022) Exosomal LINC00460/miR-503-5p/ANLN positive feedback loop aggravates pancreatic cancer progression through regulating T cell-mediated cytotoxicity and PD-1 checkpoint. Cancer Cell Int 22:390. https://doi.org/10.1186/s12935-022-02741-5
Zhan H, Xiao J, Wang P, Mo F, Li K, Guo F, Yu X, Liu X, Zhang B, Dai M, Liu H (2022) Exosomal CTCF confers cisplatin resistance in osteosarcoma by promoting autophagy via the IGF2-AS/miR-579-3p/MSH6 axis. J Oncol 2022:9390611. https://doi.org/10.1155/2022/9390611
Zhang CL, Zhu KP, Ma XL (2017) Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. Cancer Lett 396:66–75. https://doi.org/10.1016/j.canlet.2017.03.018
Zhang Y, Liu X, Wang Y, Lai S, Wang Z, Yang Y, Liu W, Wang H, Tang B (2022) The m(6)A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway. Mol Cancer 21:174. https://doi.org/10.1186/s12943-022-01647-0
Zhang Y, Yan H, Jiang Y, Chen T, Ma Z, Li F, Lin M, Xu Y, Zhang X, Zhang J, He H (2021) Long non-coding RNA IGF2-AS represses breast cancer tumorigenesis by epigenetically regulating IGF2. Exp Biol Med (Maywood) 246:371–379. https://doi.org/10.1177/1535370220966253
Zhou C, Yi C, Yi Y, Qin W, Yan Y, Dong X, Zhang X, Huang Y, Zhang R, Wei J, Ali DW, Michalak M, Chen XZ, Tang J (2020) LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes. Mol Cancer 19:118. https://doi.org/10.1186/s12943-020-01237-y
Zong S, Dai W, Guo X, Wang K (2021) LncRNA-SNHG1 promotes macrophage M2-like polarization and contributes to breast cancer growth and metastasis. Aging (Albany NY) 13:23169–23181. https://doi.org/10.18632/aging.203609
Zou J, Pei X, Xing D, Wu X, Chen S (2021) LINC00261 elevation inhibits angiogenesis and cell cycle progression of pancreatic cancer cells by upregulating SCP2 via targeting FOXP3. J Cell Mol Med 25:9826–9836. https://doi.org/10.1111/jcmm.16930
Author information
Authors and Affiliations
Contributions
YT and WH made equal contributions to conception and design. LF, JZ, and XZ performed assays. LF performed analysis. JZ was responsible for interpretation of data. YT drafted the manuscript. WH revised it critically for important intellectual content. XZ gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Corresponding author
Ethics declarations
Ethics approval
Studies involving animal experiments were approved by the animal ethical committee of the Ningbo Medical Center Lihuili Hospital.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Tian, Y., Han, W., Fu, L. et al. IGF2 is upregulated by its antisense RNA to potentiate pancreatic cancer progression. Funct Integr Genomics 23, 348 (2023). https://doi.org/10.1007/s10142-023-01277-9
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10142-023-01277-9