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

Shunxin Hao; Zhi Yao; Yifeng Liu

doi:10.1055/a-2125-7018

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2023; 55(10): 722-732
DOI: 10.1055/a-2125-7018

Original Article: Endocrine Research

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

Authors

Shunxin Hao‡

¹Department of General Surgery, Wuhan University of Science and Technology Hospital, Wuhan, China
Zhi Yao‡

¹Department of General Surgery, Wuhan University of Science and Technology Hospital, Wuhan, China
Yifeng Liu

¹Department of General Surgery, Wuhan University of Science and Technology Hospital, Wuhan, China

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

Full Text

References

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