Upregulation of LHPP by saRNA inhibited hepatocellular cancer cell proliferation and xenograft tumor growth.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Inorganic Pyrophosphatase*/metabolism ; Inorganic Pyrophosphatase*/genetics ; Cell Proliferation*/drug effects ; Carcinoma, Hepatocellular*/drug therapy ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/genetics ; Liver Neoplasms*/drug therapy ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/pathology ; Liver Neoplasms*/genetics; Humans ; Animals ; Mice ; Cell Line, Tumor ; Up-Regulation/drug effects ; Xenograft Model Antitumor Assays ; Cell Movement/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Mice, Nude

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide and no pharmacological treatment is available that can achieve complete remission of HCC. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a recently identified HCC tumor suppressor gene which plays an important role in the development of HCC and its inactivation and reactivation has been shown to result in respectively HCC tumorigenesis and suppression. Small activating RNAs (saRNAs) have been used to achieve targeted activation of therapeutic genes for the restoration of their encoded protein through the RNAa mechanism. Here we designed and validated saRNAs that could activate LHPP expression at both the mRNA and protein levels in HCC cells. Activation of LHPP by its saRNAs led to the suppression of HCC proliferation, migration and the inhibition of Akt phosphorylation. When combined with targeted anticancer drugs (e.g., regorafenib), LHPP saRNA exhibited synergistic effect in inhibiting in vitro HCC proliferation and in vivo antitumor growth in a xenograft HCC model. Findings from this study provides further evidence for a tumor suppressor role of LHPP and potential therapeutic value of restoring the expression of LHPP by saRNA for the treatment of HCC.
Competing Interests: TK, MK and L-CL are employees of Ractigen Therapeutics and named inventors of a patent application which is based on part of this work. Patent number: US20220096516A1; Patent name: Oligonucleotide molecule and application thereof in tumor therapy. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2024 Bi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Signal Transduct Target Ther. 2020 Aug 11;5(1):146. (PMID: 32782275)
Oncol Res. 2018 Mar 5;26(2):231-239. (PMID: 28911342)
Clin Liver Dis. 2023 Feb;27(1):85-102. (PMID: 36400469)
Oncol Rep. 2020 Feb;43(2):536-548. (PMID: 31894339)
Bioinformatics. 2021 Jun 16;37(10):1473-1474. (PMID: 32960970)
Semin Cancer Biol. 2019 Dec;59:80-91. (PMID: 31173856)
Target Oncol. 2017 Apr;12(2):243-253. (PMID: 28299600)
JAMA Surg. 2023 Apr 1;158(4):410-420. (PMID: 36790767)
Mol Ther Nucleic Acids. 2019 Dec 6;18:142-154. (PMID: 31546149)
Acta Biochim Biophys Sin (Shanghai). 2020 Apr 20;52(4):382-389. (PMID: 32227107)
J Cancer. 2022 Oct 31;13(14):3584-3592. (PMID: 36484014)
Acc Chem Res. 2022 Jan 4;55(1):2-12. (PMID: 34850635)
Nat Nanotechnol. 2021 Jun;16(6):630-643. (PMID: 34059811)
Nat Rev Cancer. 2021 Sep;21(9):541-557. (PMID: 34326518)
Cancers (Basel). 2021 Oct 31;13(21):. (PMID: 34771643)
Cell Death Dis. 2022 May 14;13(5):463. (PMID: 35568711)
Cancer Treat Rev. 2018 Jul;68:16-24. (PMID: 29783126)
Mol Cancer. 2017 Aug 30;16(1):149. (PMID: 28854942)
Nature. 2018 Mar 29;555(7698):678-682. (PMID: 29562234)
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17337-42. (PMID: 17085592)
J Adv Res. 2020 Jul 13;26:83-94. (PMID: 33133685)
Biosci Rep. 2019 Jul 30;39(7):. (PMID: 31262971)
Cell Cycle. 2020 Jul;19(14):1846-1854. (PMID: 32578511)
Oncogene. 2018 Jun;37(24):3216-3228. (PMID: 29511346)
J Biomol Screen. 2009 Feb;14(2):142-50. (PMID: 19196697)
J Hepatocell Carcinoma. 2021 Nov 25;8:1415-1444. (PMID: 34858888)
J Hepatol. 2018 Jul;69(1):182-236. (PMID: 29628281)
Cancer Lett. 2018 Jan 1;412:283-288. (PMID: 29050983)
Nat Genet. 2015 May;47(5):505-511. (PMID: 25822088)
Biochem Biophys Res Commun. 2018 Sep 5;503(2):1108-1114. (PMID: 29944886)
J Bioenerg Biomembr. 2021 Feb;53(1):61-71. (PMID: 33394310)
Wiley Interdiscip Rev RNA. 2011 Sep-Oct;2(5):748-60. (PMID: 21823233)
Nat Rev Drug Discov. 2020 Oct;19(10):673-694. (PMID: 32782413)
Pharmacol Rev. 2006 Sep;58(3):621-81. (PMID: 16968952)
Mol Ther Nucleic Acids. 2022 Dec 27;31:211-223. (PMID: 36700046)
Signal Transduct Target Ther. 2023 Oct 2;8(1):375. (PMID: 37779156)
Clin Cancer Res. 2020 Aug 1;26(15):3936-3946. (PMID: 32357963)
J Exp Clin Cancer Res. 2019 Nov 4;38(1):447. (PMID: 31684985)
Nat Rev Dis Primers. 2021 Jan 21;7(1):6. (PMID: 33479224)
Bioinformatics. 2016 Sep 15;32(18):2866-8. (PMID: 27153664)
Am J Cancer Res. 2015 Dec 15;6(1):97-104. (PMID: 27073727)

EC 3.6.1.1 (Inorganic Pyrophosphatase)
EC 3.6.1.1 (phospholysine phosphohistidine inorganic pyrophosphate phosphatase, human)

Date Created: 20240502 Date Completed: 20240502 Latest Revision: 20240521

20240521

PMC11065268

10.1371/journal.pone.0299522

38696452