Hsa_circ_0000106 Acts as a Tumor Promoter in Pancreatic Cancer by Targeting the MiR-455–3p/HDAC4

Abstract

Circular RNAs (circRNAs) frequently participate in pancreatic cancer (PC) progression. This study focuses on circ_0000106, a novel circRNA, and its potential function in PC development. Circ_00001106, miR-455–3p, and HDAC4 expression levels in PC were determined using qRT-PCR and immunoblotting. RNA immunoprecipitation and dual-luciferase reporter assays were performed to verify their binding interactions. Loss-of-function assays, including CCK-8, colony formation, and transwell assays, were used to estimate the proliferative and migratory properties of PC cells. A nude mouse model was constructed to assess the influence of circ_0000106 on tumor formation in vivo. A pronounced elevation of circ_0000106 and HDAC4 and a reduction of miR-455–3p in PC were observed. Circ_0000106 was prone to binding to miR-455–3p, and miR-455–3p further targeted HDAC4. Functionally, the proliferative and migratory properties of PC cells were dampened by the loss of circ_0000106 or HDAC4 and could be potentiated by miR-455–3p inhibition. Moreover, the knockdown of circ_0000106 delayed tumor growth in vivo. Additionally, the downregulation of miR-455–3p attenuated the repressive effects of circ_0000106 deficiency on PC cell migration and proliferation. Loss of HDAC4 exerted similar mitigative effects on miR-455–3p downregulation-stimulated PC cells. In conclusion, circ_0000106 promotes tumor migration and growth in PC by targeting the miR-455–3p/HDAC4 axis. These results suggest that the circ_0000106/miR-455–3p/HDAC4 network could be regarded as a latent target for PC treatment.

Key words

pancreatic cancer - circ_0000106 - miR-455–3p - HDAC4 - proliferation - migration

Publication History

Received: 20 February 2023

Accepted after revision: 30 June 2023

Article published online:
08 August 2023

• References

• 1 Kamisawa T, Wood LD, Itoi T. et al. Pancreatic cancer. Lancet 2016; 388: 73-85
• 2 Miller KD, Fidler-Benaoudia M, Keegan TH. et al. Cancer statistics for adolescents and young adults, 2020. CA Cancer J Clin 2020; 70: 443-459
• 3 McGuigan A, Kelly P, Turkington RC. et al. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018; 24: 4846-4861
• 4 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69: 7-34
• 5 Kelly KN, Macedo FI, Merchant NB. Neoadjuvant therapy: when should it be used for pancreatic cancer?. Adv Surg 2020; 54: 49-68
• 6 Meng S, Zhou H, Feng Z. et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer 2017; 16: 94
• 7 Kulcheski FR, Christoff AP, Margis R. Circular RNAs are miRNA sponges and can be used as a new class of biomarker. J Biotechnol 2016; 238: 42-51
• 8 Liu P, Wang Z, Ou X. et al. The FUS/circEZH2/KLF5/feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition. Mol Cancer 2022; 21: 198
• 9 Zhang W, Liu T, Li T. et al. Hsa_circRNA_102002 facilitates metastasis of papillary thyroid cancer through regulating miR-488-3p/HAS2 axis. Cancer Gene Ther 2021; 28: 279-293
• 10 Zhang R, Zhu W, Ma C. et al. Silencing of circRNA circ_0001666 represses EMT in pancreatic cancer through upregulating miR-1251 and downregulating SOX4. Front Mol Biosci 2021; 8: 684866
• 11 Yang F, Liu DY, Guo JT. et al. Circular RNA circ-LDLRAD3 as a biomarker in diagnosis of pancreatic cancer. World J Gastroenterol 2017; 23: 8345-8354
• 12 Qu S, Hao X, Song W. et al. Circular RNA circRHOT1 is upregulated and promotes cell proliferation and invasion in pancreatic cancer. Epigenomics 2019; 11: 53-63
• 13 Hill M, Tran N. miRNA interplay: mechanisms and consequences in cancer. Dis Model Mech 2021; 14: dmm047662
• 14 He B, Zhao Z, Cai Q. et al. miRNA-based biomarkers, therapies, and resistance in Cancer. Int J Biol Sci 2020; 16: 2628-2647
• 15 Fei X, Jin HY, Gao Y. et al. Hsa-miR-10a-5p promotes pancreatic cancer growth by BDNF/SEMA4C pathway. J Biol Regul Homeost Agents 2020; 34: 927-934
• 16 Jingyang Z, Jinhui C, Lu X. et al. Mir-320b inhibits pancreatic cancer cell proliferation by targeting FOXM1. Curr Pharm Biotechnol 2021; 22: 1106-1113
• 17 Li X, Hou YS. MiR-4282 contributes to inhibit pancreatic cancer metastasis by negatively interacting with ABCB5. Eur Rev Med Pharmacol Sci 2020; 24: 9915-9923
• 18 Sun Y, Wang Y, Yang H. et al. miR-455-3p functions as a tumor suppressor in colorectal cancer and inhibits cell proliferation by targeting TPT1. Int J Clin Exp Pathol 2018; 11: 2522-2529
• 19 Gao X, Zhao H, Diao C. et al. miR-455-3p serves as prognostic factor and regulates the proliferation and migration of non-small cell lung cancer through targeting HOXB5. Biochem Biophys Res Commun 2018; 495: 1074-1080
• 20 Zhan T, Zhu Q, Han Z. et al. miR-455-3p Functions as a tumor suppressor by restraining Wnt/β-catenin signaling via TAZ in pancreatic cancer. Cancer Manag Res 2020; 12: 1483-1492
• 21 Zhan T, Huang X, Tian X. et al. Downregulation of microRNA-455-3p links to proliferation and drug resistance of pancreatic cancer cells via targeting TAZ. Mol Ther Nucleic Acids 2018; 10: 215-226
• 22 Shi Y, Liu C. Circular RNA hsa_circ_0043278 inhibits breast cancer progression via the miR-455-3p/EI24 signalling pathway. BMC Cancer 2021; 21: 1249
• 23 Liao Y, Yang D, Luo H. et al. CircSEC24A promotes tumor progression through sequestering miR-455-3p in hepatocellular carcinoma. Neoplasma 2021; 210305N285
• 24 Huang X, Shen X, Peng L. et al. CircCSNK1G1 Contributes to the development of colorectal cancer by increasing the expression of MYO6 via competitively targeting miR-455-3p. Cancer Manag Res 2020; 12: 9563-9575
• 25 Zhu J, Zhou Y, Zhu S. et al. circRNA circ_102049 Implicates in pancreatic ductal adenocarcinoma progression through activating CD80 by targeting miR-455-3p. Mediators Inflamm 2021; 8819990
• 26 Cuttini E, Goi C, Pellarin E. et al. HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications. Front Mol Biosci 2023; 10: 1116660
• 27 Zeng LS, Yang XZ, Wen YF. et al. Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma. Aging (Albany NY) 2016; 8: 1236-1249
• 28 Amodio N, Stamato MA, Gullà AM. et al. Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma. Mol Cancer Ther 2016; 15: 1364-1375
• 29 Cheng C, Yang J, Li SW. et al. HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell Death Dis 2021; 12: 137
• 30 Zang WJ, Hu YL, Qian CY. et al. HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3. Br J Cancer 2022; 127: 237-248
• 31 Yang J, Chheda C, Lim A. et al. HDAC4 mediates smoking-induced pancreatic cancer metastasis. Pancreas 2022; 51: 190-195
• 32 Zhu L, Staley C, Kooby D. et al. Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy. Cancer Lett 2017; 388: 139-148
• 33 Chen J, Wu Y, Luo X. et al. Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer. Theranostics 2021; 11: 7507-7526
• 34 Zhu P, Ge N, Liu D. et al. Preliminary investigation of the function of hsa_circ_0006215 in pancreatic cancer. Oncol Lett 2018; 16: 603-611
• 35 Han X, Fang Y, Chen P. et al. Upregulated circRNA hsa_circ_0071036 promotes tumourigenesis of pancreatic cancer by sponging miR-489 and predicts unfavorable characteristics and prognosis. Cell Cycle 2021; 20: 369-382
• 36 Xing C, Ye H, Wang W. et al. Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression. Artif Cells Nanomed Biotechnol 2019; 47: 3920-3928
• 37 Zhao Y, Yan M, Yun Y. et al. MicroRNA-455-3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. Oncol Rep 2017; 37: 2449-2458
• 38 Meng C, Liu K, Cai X. et al. Mechanism of miR-455-3 in suppressing epithelial-mesenchymal transition and angiogenesis of non-small cell lung cancer cells. Cell Stress Chaperones 2021; 27: 107-117
• 39 Zheng J, Lin Z, Zhang L. et al. MicroRNA-455-3p inhibits tumor cell proliferation and induces apoptosis in HCT116 human colon cancer cells. Med Sci Monit 2016; 22: 4431-4437
• 40 Guo J, Liu C, Wang W. et al. Identification of serum miR-1915-3p and miR-455-3p as biomarkers for breast cancer. PLoS One 2018; 13: e0200716
• 41 Yi X, Wang Y, Xu S. MiR-455-3p downregulation facilitates cell proliferation and invasion and predicts poor prognosis of osteosarcoma. J Orthop Surg Res 2020; 15: 454
• 42 Shao C, Guo K, Xu L. et al. Senescence marker protein 30 inhibits tumor growth by reducing HDAC4 expression in non-small cell lung cancer. Transl Lung Cancer Res 2021; 10: 4558-4573
• 43 Spaety ME, Gries A, Badie A. et al. HDAC4 levels control sensibility toward cisplatin in gastric cancer via the p53-p73/BIK pathway. Cancers (Basel) 2019; 11: 1747
• 44 Wilson AJ, Byun DS, Nasser S. et al. HDAC4 promotes growth of colon cancer cells via repression of p21. Mol Biol Cell 2008; 19: 4062-4075
• 45 Barneda-Zahonero B, Parra M. Histone deacetylases and cancer. Mol Oncol 2012; 6: 579-589
• 46 Kang ZH, Wang CY, Zhang WL. et al. Histone deacetylase HDAC4 promotes gastric cancer SGC-7901 cells progression via p21 repression. PLoS One 2014; 9: e98894
• 47 Lee HS, Park SB, Kim SA. et al. A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance. Sci Rep 2017; 7: 41615
• 48 Ouaïssi M, Cabral S, Tavares J. et al. Histone deacetylase (HDAC) encoding gene expression in pancreatic cancer cell lines and cell sensitivity to HDAC inhibitors. Cancer Biol Ther 2008; 7: 523-531
• 49 Chao MW, Chang LH, Tu HJ. et al. Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status. Clin Epigenetics 2019; 11: 85
• 50 Ji M, Li Z, Lin Z. et al. Antitumor activity of the novel HDAC inhibitor CUDC-101 combined with gemcitabine in pancreatic cancer. Am J Cancer Res 2018; 8: 2402-2418
• 51 Xiao Y. Construction of a circRNA-miRNA-mRNA network to explore the pathogenesis and treatment of pancreatic ductal adenocarcinoma. J Cell Biochem 2020; 121: 394-406
• 52 Parra M. Class IIa HDACs – new insights into their functions in physiology and pathology. Febs j 2015; 282: 1736-1744
• 53 Wang Z, Qin G, Zhao TC. HDAC4: mechanism of regulation and biological functions. Epigenomics 2014; 6: 139-150
• 54 Wu H, Liu C, Yang Q. et al. MIR145-3p promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting HDAC4. Autophagy 2020; 16: 683-697
• 55 Jin K, Zhao W, Xie X. et al. MiR-520b restrains cell growth by targeting HDAC4 in lung cancer. Thorac Cancer 2018; 9: 1249-1254
• 56 Zhou C, Yi C, Yi Y. et al. 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 2020; 19: 118