Temporin-GHaK Exhibits Antineoplastic Activity Against Human Lung Adenocarcinoma by Inhibiting the Wnt Signaling Pathway Through MiRNA-4516

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Jun 27

PMID 38930863

Authors

Yueli Liu

Hui Liu

Jiaxin Zhang

Yingxia Zhang

Affiliations

Soon will be listed here.

Abstract

(1) Background: GHaK is derived from the antimicrobial peptide temporin-GHa by substituting the amino acid H with K to enhance its bactericidal activity. The present research aims to broaden the pharmacological potential of GHaK by exploring its antineoplastic activity against human lung adenocarcinoma. (2) Methods: The cell viability, migration, invasion, apoptosis, and cell cycle of A549 and PC-9 cells were tested after GHaK treatment. miRNA sequencing, RT-PCR, Western blotting, and luciferase reporter gene assay were further performed to reveal the potential mechanism. (3) Results: GHaK significantly suppressed cell viability, migration, and invasion; induced apoptosis; and caused cell cycle arrest in the G2/M and S phase in PC-9 and A549 cells, respectively. The miRNA sequencing results show a total of 161 up-regulated and 115 down-regulated miRNAs. Furthermore, the study identified six up-regulated miRNAs (miR-4516, miR-4284, miR-204-5p, miR-12136, miR-4463, and miR-1296-3p) and their inhibitory effects on the expressions of target genes (Wnt 8B, FZD2, DVL3, and FOSL1) caused by miR-4516 directly interacting with Wnt 8B. Western blotting revealed the down-regulation of p-GSK-3β, along with a decreased expressions of cyclin A1 and CDK2 in A549 cells and cyclin B1 and CDK1 in PC-9 cells. (4) Conclusions: Temporin-GHaK exhibits antineoplastic activity against human lung adenocarcinoma by inhibiting the Wnt signaling pathway through miRNA-4516.

References

Wu X, Wang Y, Cai X, Dong Y, Cui Q, Zhou Y . RNF115 promotes lung adenocarcinoma through Wnt/β-catenin pathway activation by mediating APC ubiquitination. Cancer Metab. 2021; 9(1):7. PMC: 7842072. DOI: 10.1186/s40170-021-00243-y. View

Wan H, Lin T, Shan M, Lu J, Guo Z . LINC00491 Facilitates Tumor Progression of Lung Adenocarcinoma via Wnt/β-Catenin-Signaling Pathway by Regulating MTSS1 Ubiquitination. Cells. 2022; 11(23). PMC: 9738320. DOI: 10.3390/cells11233737. View

Reck M, Rabe K . Precision Diagnosis and Treatment for Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 377(9):849-861. DOI: 10.1056/NEJMra1703413. View

Wang Z, Xu R . lncRNA PART1 Promotes Breast Cancer Cell Progression by Directly Targeting miR-4516. Cancer Manag Res. 2020; 12:7753-7760. PMC: 7457826. DOI: 10.2147/CMAR.S249296. View

Xie Z, Wei H, Meng J, Cheng T, Song Y, Wang M . The Analogs of Temporin-GHa Exhibit a Broader Spectrum of Antimicrobial Activity and a Stronger Antibiofilm Potential against . Molecules. 2019; 24(22). PMC: 6891419. DOI: 10.3390/molecules24224173. View

Mishra B, Reiling S, Zarena D, Wang G . Host defense antimicrobial peptides as antibiotics: design and application strategies. Curr Opin Chem Biol. 2017; 38:87-96. PMC: 5494204. DOI: 10.1016/j.cbpa.2017.03.014. View

Zhong C, Chen M, Chen Y, Yao F, Fang W . Loss of DSTYK activates Wnt/β-catenin signaling and glycolysis in lung adenocarcinoma. Cell Death Dis. 2021; 12(12):1122. PMC: 8636471. DOI: 10.1038/s41419-021-04385-1. View

Ju X, Fan D, Kong L, Yang Q, Zhu Y, Zhang S . Antimicrobial Peptide Brevinin-1RL1 from Frog Skin Secretion Induces Apoptosis and Necrosis of Tumor Cells. Molecules. 2021; 26(7). PMC: 8038347. DOI: 10.3390/molecules26072059. View

Selvarathinam K, Subramani P, Thekkumalai M, Vilwanathan R, Selvarajan R, Abia A . Wnt Signaling Pathway Collapse upon β-Catenin Destruction by a Novel Antimicrobial Peptide SKACP003: Unveiling the Molecular Mechanism and Genetic Activities Using Breast Cancer Cell Lines. Molecules. 2023; 28(3). PMC: 9920962. DOI: 10.3390/molecules28030930. View

10.

Al-Darraji M, Jasim S, Salah Aldeen O, Ghasemian A, Rasheed M . The Effect of LL37 Antimicrobial Peptide on FOXE1 and lncRNA PTCSC 2 Genes Expression in Colorectal Cancer (CRC) and Normal Cells. Asian Pac J Cancer Prev. 2022; 23(10):3437-3442. PMC: 9924353. DOI: 10.31557/APJCP.2022.23.10.3437. View

11.

Li Q, Wang W, Yang T, Li D, Huang Y, Bai G . LINC00520 up-regulates SOX5 to promote cell proliferation and invasion by miR-4516 in human hepatocellular carcinoma. Biol Chem. 2022; 403(7):665-678. DOI: 10.1515/hsz-2021-0316. View

12.

Maijaroen S, Klaynongsruang S, Roytrakul S, Konkchaiyaphum M, Taemaitree L, Jangpromma N . An Integrated Proteomics and Bioinformatics Analysis of the Anticancer Properties of RT2 Antimicrobial Peptide on Human Colon Cancer (Caco-2) Cells. Molecules. 2022; 27(4). PMC: 8880037. DOI: 10.3390/molecules27041426. View

13.

Wei H, Xie Z, Tan X, Guo R, Song Y, Xie X . Temporin-Like Peptides Show Antimicrobial and Anti-Biofilm Activities against with Reduced Hemolysis. Molecules. 2020; 25(23). PMC: 7730238. DOI: 10.3390/molecules25235724. View

14.

Sanchez-Cespedes M . Lung cancer biology: a genetic and genomic perspective. Clin Transl Oncol. 2009; 11(5):263-9. DOI: 10.1007/s12094-009-0353-7. View

15.

Hancock R, Sahl H . Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006; 24(12):1551-7. DOI: 10.1038/nbt1267. View

16.

Roman M, Lopez I, Guruceaga E, Baraibar I, Ecay M, Collantes M . Inhibitor of Differentiation-1 Sustains Mutant -Driven Progression, Maintenance, and Metastasis of Lung Adenocarcinoma via Regulation of a FOSL1 Network. Cancer Res. 2018; 79(3):625-638. DOI: 10.1158/0008-5472.CAN-18-1479. View

17.

Chen S, Xu M, Zhao J, Shen J, Li J, Liu Y . MicroRNA-4516 suppresses pancreatic cancer development via negatively regulating orthodenticle homeobox 1. Int J Biol Sci. 2020; 16(12):2159-2169. PMC: 7294951. DOI: 10.7150/ijbs.45933. View

18.

Dong Z, Luo W, Zhong H, Wang M, Song Y, Deng S . Molecular cloning and characterization of antimicrobial peptides from skin of Hylarana guentheri. Acta Biochim Biophys Sin (Shanghai). 2017; 49(5):450-457. DOI: 10.1093/abbs/gmx023. View

19.

Guan X, Liang J, Xiang Y, Li T, Zhong X . BARX1 repressed FOXF1 expression and activated Wnt/β-catenin signaling pathway to drive lung adenocarcinoma. Int J Biol Macromol. 2024; 261(Pt 2):129717. DOI: 10.1016/j.ijbiomac.2024.129717. View

20.

Kim J, Kim B, Jang Y, Kang S, Lee J, Cho N . The stromal loss of miR-4516 promotes the FOSL1-dependent proliferation and malignancy of triple negative breast cancer. Cancer Lett. 2019; 469:256-265. DOI: 10.1016/j.canlet.2019.10.039. View