Potential roles of NEDD4 and NEDD4L and their utility as therapeutic targets in high‑incidence adult male cancers (Review)

Alrosan,Amjad Z.; Alrosan,Khaled; Heilat,Ghaith B.; Alsharedeh,Rawan; Abudalo,Rawan; Oqal,Muna; Alqudah,Abdelrahim; Elmaghrabi,Yasmin A.

doi:10.3892/mco.2023.2664

Potential roles of NEDD4 and NEDD4L and their utility as therapeutic targets in high‑incidence adult male cancers (Review)

Authors:
- Amjad Z. Alrosan
- Khaled Alrosan
- Ghaith B. Heilat
- Rawan Alsharedeh
- Rawan Abudalo
- Muna Oqal
- Abdelrahim Alqudah
- Yasmin A. Elmaghrabi
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Affiliations: Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa 13133, Jordan, Department of General Surgery and Urology, Faculty of Medicine, The Jordan University of Science and Technology, Irbid 22110, Jordan, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The Yarmouk University, Irbid 21163, Jordan, Department of Pharmaceutical Technology, Faculty of Pharmacy, The Hashemite University, Zarqa 13133, Jordan, Wizard Pharmacy Willetton, Perth 6155, Western Australia
Published online on: July 18, 2023 https://doi.org/10.3892/mco.2023.2664
Article Number: 68
Copyright: © Alrosan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The term ‘cancer’ refers to >100 disorders that progressively manifest over time and are characterized by uncontrolled cell division. Although malignant growth can occur in virtually any human tissue, the underlying mechanisms underlying all forms of cancer are consistent. The International Agency for Research on Cancer's annual GLOBOCAN 2020 report provided an update on the global cancer incidence and mortality. Excluding non‑melanoma skin cancer, the report predicts that there will be 19.3 million new cancer cases and >10 million cancer‑related fatalities in 2023. Lung, prostate, and colon cancers are the most prevalent and lethal cancers in males. It was recognized that post‑translational modifications (PTMs) of proteins are necessary for almost all cellular biological processes, as well as in cancer development and metastasis to other bodily organs. Thus, PTMs have a considerable impact on how proteins behave. Various PTMs may have harmful roles by affecting the hallmarks of cancer, metabolism and the regulation of the tumor microenvironment. PTMs and genetic changes/mutations are essential in carcinogenesis and cancer development. A pivotal PTM mechanism is protein ubiquitination. Of note, the rate‑limiting stage of the protein ubiquitination cascade is hypothesized to be E3‑ligase‑mediated ubiquitination. Numerous studies revealed that the neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) E3 ligase is among the E3 ubiquitin ligases that have essential roles in cellular processes. It regulates protein degradation and substrate ubiquitination. In addition, it has been shown that NEDD4 primarily functions as an oncogene in various malignancies but can also act as a tumor suppressor in certain types of tumor. In the present review, the roles of NEDD4 as an anticancer protein in various high‑incidence male malignancies and the significance of NEDD4 as a potential cancer therapeutic target are discussed. In addition, the targeting of NEDD4 as a therapeutic strategy for the treatment of human malignancies is explored.

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1	Cooper GM: The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates. The Development and Causes of Cancer. https://www.ncbi.nlm.nih.gov/books/NBK9963/. 2000.
2	Hanahan D: Hallmarks of cancer: New dimensions. Cancer Discov. 12:31–46. 2022.PubMed/NCBI View Article : Google Scholar
3	American Cancer Society. Cancer Statistics Center. http://cancerstatisticscenter.cancer.org. Accessed Dec 25, 2022.
4	World Health Organization (WHO): Editorial Style Manual WHO, Geneva, p83-91, 1993.
5	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
6	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2022. CA Cancer J Clin. 72:7–33. 2022.PubMed/NCBI View Article : Google Scholar
7	Bertram JS: The molecular biology of cancer. Mol Aspects Med. 21:167–223. 2000.PubMed/NCBI View Article : Google Scholar
8	Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A, Garmpis N, Diakosavvas M, Angelou K, Tsatsaris G, Pagkalos A, et al: Role of oncogenes and tumor-suppressor genes in carcinogenesis: A review. Anticancer Res. 40:6009–6015. 2020.PubMed/NCBI View Article : Google Scholar
9	Welti J, Loges S, Dimmeler S and Carmeliet P: Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 123:3190–3200. 2013.PubMed/NCBI View Article : Google Scholar
10	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011.PubMed/NCBI View Article : Google Scholar
11	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000.PubMed/NCBI View Article : Google Scholar
12	Kamali H, Golmohammadzadeh S, Zare H, Nosrati R, Fereidouni M and Safarpour H: The recent advancements in the early detection of cancer biomarkers by DNAzyme-assisted aptasensors. J Nanobiotechnology. 20(438)2022.PubMed/NCBI View Article : Google Scholar
13	Pan S and Chen R: Pathological implication of protein post-translational modifications in cancer. Mol Aspects Med. 86(101097)2022.PubMed/NCBI View Article : Google Scholar
14	Hershko A and Ciechanover A: The ubiquitin system. Annu Rev Biochem. 67:425–479. 1998.PubMed/NCBI View Article : Google Scholar
15	Weissman AM: Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol. 2:169–178. 2001.PubMed/NCBI View Article : Google Scholar
16	Komander D and Rape M: The ubiquitin code. Annu Rev Biochem. 81:203–229. 2012.PubMed/NCBI View Article : Google Scholar
17	Salas-Lloret D and González-Prieto R: Insights in post-translational modifications: Ubiquitin and SUMO. Int J Mol Sci. 23(3281)2022.PubMed/NCBI View Article : Google Scholar
18	Liebl MP and Hoppe T: It's all about talking: Two-way communication between proteasomal and lysosomal degradation pathways via ubiquitin. Am J Physiol Cell Physiol. 311:C166–C178. 2016.PubMed/NCBI View Article : Google Scholar
19	Tu Y, Chen C, Pan J, Xu J, Zhou ZG and Wang CY: The Ubiquitin Proteasome Pathway (UPP) in the regulation of cell cycle control and DNA damage repair and its implication in tumorigenesis. Int J Clin Exp Pathol. 5:726–738. 2012.PubMed/NCBI
20	Klionsky DJ and Schulman BA: Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat Struct Mol Biol. 21:336–345. 2014.PubMed/NCBI View Article : Google Scholar
21	Kerscher O, Felberbaum R and Hochstrasser M: Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 22:159–180. 2006.PubMed/NCBI View Article : Google Scholar
22	Ciechanover A and Kwon YT: Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies. Exp Mol Med. 47(e147)2015.PubMed/NCBI View Article : Google Scholar
23	Berndsen CE and Wolberger C: New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol. 21:301–307. 2014.PubMed/NCBI View Article : Google Scholar
24	Kravtsova-Ivantsiv Y and Ciechanover A: Non-canonical ubiquitin-based signals for proteasomal degradation. J Cell Sci. 125(Pt 3):539–548. 2012.PubMed/NCBI View Article : Google Scholar
25	Buetow L and Huang DT: Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol. 17:626–642. 2016.PubMed/NCBI View Article : Google Scholar
26	Rotin D and Kumar S: Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol. 10:398–409. 2009.PubMed/NCBI View Article : Google Scholar
27	Metzger MB, Hristova VA and Weissman AM: HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci. 125(Pt 3):531–537. 2012.PubMed/NCBI View Article : Google Scholar
28	Joazeiro CA and Weissman AM: RING finger proteins: Mediators of ubiquitin ligase activity. Cell. 102:549–552. 2000.PubMed/NCBI View Article : Google Scholar
29	Bernassola F, Karin M, Ciechanover A and Melino G: The HECT family of E3 ubiquitin ligases: Multiple players in cancer development. Cancer Cell. 14:10–21. 2008.PubMed/NCBI View Article : Google Scholar
30	Dove KK, Stieglitz B, Duncan ED, Rittinger K and Klevit RE: Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms. EMBO Rep. 17:1221–1235. 2016.PubMed/NCBI View Article : Google Scholar
31	Li W and Ye Y: Polyubiquitin chains: Functions, structures, and mechanisms. Cell Mol Life Sci. 65:2397–2406. 2008.PubMed/NCBI View Article : Google Scholar
32	Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S and Cook DI: Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. Proc Natl Acad Sci USA. 95:7169–7173. 1998.PubMed/NCBI View Article : Google Scholar
33	Goulet CC, Volk KA, Adams CM, Prince LS, Stokes JB and Snyder PM: Inhibition of the epithelial Na+ channel by interaction of Nedd4 with a PY motif deleted in Liddle's syndrome. J Biol Chem. 273:30012–30017. 1998.PubMed/NCBI View Article : Google Scholar
34	Harvey KF, Dinudom A, Komwatana P, Jolliffe CN, Day ML, Parasivam G, Cook DI and Kumar S: All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na+. J Biol Chem. 274:12525–12530. 1999.PubMed/NCBI View Article : Google Scholar
35	Harvey KF, Dinudom A, Cook DI and Kumar S: The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J Biol Chem. 276:8597–8601. 2001.PubMed/NCBI View Article : Google Scholar
36	Kanelis V, Farrow NA, Kay LE, Rotin D and Forman-Kay JD: NMR studies of tandem WW domains of Nedd4 in complex with a PY motif-containing region of the epithelial sodium channel. Biochem Cell Biol. 76:341–350. 1998.PubMed/NCBI View Article : Google Scholar
37	Ingham RJ, Gish G and Pawson T: The Nedd4 family of E3 ubiquitin ligases: Functional diversity within a common modular architecture. Oncogene. 23:1972–1984. 2004.PubMed/NCBI View Article : Google Scholar
38	Dodson EJ, Fishbain-Yoskovitz V, Rotem-Bamberger S and Schueler-Furman O: Versatile communication strategies among tandem WW domain repeats. Exp Biol Med (Maywood). 240:351–360. 2015.PubMed/NCBI View Article : Google Scholar
39	Scheffner M and Kumar S: Mammalian HECT ubiquitin-protein ligases: Biological and pathophysiological aspects. Biochim Biophys Acta. 1843:61–74. 2014.PubMed/NCBI View Article : Google Scholar
40	Lee IH, Dinudom A, Sanchez-Perez A, Kumar S and Cook DI: Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. J Biol Chem. 282:29866–29873. 2007.PubMed/NCBI View Article : Google Scholar
41	Goel P, Manning JA and Kumar S: NEDD4-2 (NEDD4L): The ubiquitin ligase for multiple membrane proteins. Gene. 557:1–10. 2015.PubMed/NCBI View Article : Google Scholar
42	Lu X, Xu H, Xu J, Lu S, You S, Huang X, Zhang N and Zhang L: The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response. Front Physiol. 13(968927)2022.PubMed/NCBI View Article : Google Scholar
43	Chaugule VK and Walden H: Specificity and disease in the ubiquitin system. Biochem Soc Trans. 44:212–227. 2016.PubMed/NCBI View Article : Google Scholar
44	Herrmann J, Soares SM, Lerman LO and Lerman A: Potential role of the ubiquitin-proteasome system in atherosclerosis: Aspects of a protein quality disease. J Am Coll Cardiol. 51:2003–2010. 2008.PubMed/NCBI View Article : Google Scholar
45	Potjewyd FM and Axtman AD: Exploration of Aberrant E3 ligases implicated in Alzheimer's disease and development of chemical tools to modulate their function. Front Cell Neurosci. 15(768655)2021.PubMed/NCBI View Article : Google Scholar
46	Sun T, Liu Z and Yang Q: The role of ubiquitination and deubiquitination in cancer metabolism. Mol Cancer. 19(146)2020.PubMed/NCBI View Article : Google Scholar
47	Petroski MD: The ubiquitin system, disease, and drug discovery. BMC Biochem. 9 (Suppl 1)(S7)2008.PubMed/NCBI View Article : Google Scholar
48	Orlowski RZ and Kuhn DJ: Proteasome inhibitors in cancer therapy: Lessons from the first decade. Clin Cancer Res. 14:1649–1657. 2008.PubMed/NCBI View Article : Google Scholar
49	Thandra KC and Barsouk A, Saginala K, Aluru JS and Barsouk A: Epidemiology of lung cancer. Contemp Oncol (Pozn). 25:45–52. 2021.PubMed/NCBI View Article : Google Scholar
50	Zhang J, Cao R, Lian C, Cao T, Shi Y, Ma J, Wang P and Xia J: Nitidine chloride suppresses NEDD4 expression in lung cancer cells. Aging (Albany NY). 13:782–793. 2020.PubMed/NCBI View Article : Google Scholar
51	Rajdev K, Siddiqui AH, Ibrahim U, Patibandla P, Khan T and El-Sayegh D: An unusually aggressive large cell carcinoma of the lung: Undiagnosed until autopsy. Cureus. 10(e2202)2018.PubMed/NCBI View Article : Google Scholar
52	Amodio N, Scrima M, Palaia L, Salman AN, Quintiero A, Franco R, Botti G, Pirozzi P, Rocco G, De Rosa N and Viglietto G: Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas. Am J Pathol. 177:2622–2634. 2010.PubMed/NCBI View Article : Google Scholar
53	Zhang W, Zhang R, Zeng Y, Li Y, Chen Y, Zhou J, Zhang Y, Wang A, Zhu J, Liu Z, et al: ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L. Cell Death Dis. 12(755)2021.PubMed/NCBI View Article : Google Scholar
54	Song YH, Zhang CQ, Chen FF and Lin XY: Upregulation of neural precursor cell expressed developmentally downregulated 4-1 is associated with poor prognosis and chemoresistance in lung adenocarcinoma. Chin Med J (Engl). 131:16–24. 2018.PubMed/NCBI View Article : Google Scholar
55	Chen Z, Fillmore CM, Hammerman PS, Kim CF and Wong KK: Non-small-cell lung cancers: A heterogeneous set of diseases. Nat Rev Cancer. 14:535–546. 2014.PubMed/NCBI View Article : Google Scholar
56	He H, Huang C, Chen Z, Huang H, Wang X and Chen J: An outlined review for the role of Nedd4-1 and Nedd4-2 in lung disorders. Biomed Pharmacother. 125(109983)2020.PubMed/NCBI View Article : Google Scholar
57	Georgescu MM: PTEN tumor suppressor network in PI3K-Akt pathway control. Genes Cancer. 1:1170–1177. 2010.PubMed/NCBI View Article : Google Scholar
58	Wei C, Lin M, Jinjun B, Su F, Dan C, Yan C, Jie Y, Jin Z, Zi-Chun H and Wu Y: Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms. Mol Biol Cell. 26:1044–1057. 2015.PubMed/NCBI View Article : Google Scholar
59	Shao G, Wang R, Sun A, Wei J, Peng K, Dai Q, Yang W and Lin Q: The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells. Mol Cancer. 17(24)2018.PubMed/NCBI View Article : Google Scholar
60	Sakashita H, Inoue H, Akamine S, Ishida T, Inase N, Shirao K, Mori M and Mimori K: Identification of the NEDD4L gene as a prognostic marker by integrated microarray analysis of copy number and gene expression profiling in non-small cell lung cancer. Ann Surg Oncol. 20 (Suppl 3):S590–S598. 2013.PubMed/NCBI View Article : Google Scholar
61	Li G, Song Z, Wu C, Li X, Zhao L, Tong B, Guo Z, Sun M, Zhao J, Zhang H, et al: Downregulation of NEDD4L by EGFR signaling promotes the development of lung adenocarcinoma. J Transl Med. 20(47)2022.PubMed/NCBI View Article : Google Scholar
62	Li R, Hu Z, Sun SY, Chen ZG, Owonikoko TK, Sica GL, Ramalingam SS, Curran WJ, Khuri FR and Deng X: Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol Cancer Ther. 12:2200–2212. 2013.PubMed/NCBI View Article : Google Scholar
63	Xie S, Xia L, Song Y, Liu H, Wang ZW and Zhu X: Insights into the biological role of NEDD4L E3 ubiquitin ligase in human cancers. Front Oncol. 11(774648)2021.PubMed/NCBI View Article : Google Scholar
64	Lai XN, Li J, Tang LB, Chen WT, Zhang L and Xiong LX: MiRNAs and LncRNAs: Dual roles in TGF-β signaling-regulated metastasis in lung cancer. Int J Mol Sci. 21(1193)2020.PubMed/NCBI View Article : Google Scholar
65	Qu MH, Han C, Srivastava AK, Cui T, Zou N, Gao ZQ and Wang QE: miR-93 promotes TGF-β-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells. Tumour Biol. 37:5645–5651. 2016.PubMed/NCBI View Article : Google Scholar
66	Bai X, Jing L, Li Y, Li Y, Luo S, Wang S, Zhou J, Liu Z and Diao A: TMEPAI inhibits TGF-β signaling by promoting lysosome degradation of TGF-β receptor and contributes to lung cancer development. Cell Signal. 26:2030–2039. 2014.PubMed/NCBI View Article : Google Scholar
67	Sun A, Zhu J, Xia S, Li Y, Wu T, Shao G, Yang W and Lin Q: MEKK5 interacts with and negatively regulates the E3 ubiquitin ligase NEDD4 for mediating lung cancer cell migration. Life (Basel). 11(1153)2021.PubMed/NCBI View Article : Google Scholar
68	Saginala K and Barsouk A, Aluru JS, Rawla P, Padala SA and Barsouk A: Epidemiology of bladder cancer. Med Sci (Basel). 8(15)2020.PubMed/NCBI View Article : Google Scholar
69	Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME and Lotan Y: Bladder cancer. Nat Rev Dis Primers. 3(17022)2017.PubMed/NCBI View Article : Google Scholar
70	Wen W, Li J, Wang L, Xing Y, Li X, Ruan H, Xi X, Xiong J and Kuang R: Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells. Cell Cycle. 16:1509–1514. 2017.PubMed/NCBI View Article : Google Scholar
71	Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, et al: NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 128:129–139. 2007.PubMed/NCBI View Article : Google Scholar
72	Mao M, Yang L, Hu J, Liu B, Zhang X, Liu Y, Wang P and Li H: Oncogenic E3 ubiquitin ligase NEDD4 binds to KLF8 and regulates the microRNA-132/NRF2 axis in bladder cancer. Exp Mol Med. 54:47–60. 2022.PubMed/NCBI View Article : Google Scholar
73	Jing W, Wang G, Cui Z, Xiong G, Jiang X, Li Y, Li W, Han B, Chen S and Shi B: FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell-mediated bladder cancer immune surveillance. Cancer Res. 82:114–129. 2022.PubMed/NCBI View Article : Google Scholar
74	Zhao H, Zhang J, Fu X, Mao D, Qi X, Liang S, Meng G, Song Z, Yang R, Guo Z, et al: Integrated bioinformatics analysis of the NEDD4 family reveals a prognostic value of NEDD4L in clear-cell renal cell cancer. PeerJ. 9(e11880)2021.PubMed/NCBI View Article : Google Scholar
75	Hu XY, Xu YM, Fu Q, Yu JJ and Huang J: Nedd4L expression is downregulated in prostate cancer compared to benign prostatic hyperplasia. Eur J Surg Oncol. 35:527–531. 2009.PubMed/NCBI View Article : Google Scholar
76	Negoita S, Feuer EJ, Mariotto A, Cronin KA, Petkov VI, Hussey SK, Benard V, Henley SJ, Anderson RN, Fedewa S, et al: Annual report to the nation on the status of cancer, part II: Recent changes in prostate cancer trends and disease characteristics. Cancer. 124:2801–2814. 2018.PubMed/NCBI View Article : Google Scholar
77	Butler SS, Muralidhar V, Zhao SG, Sanford NN, Franco I, Fullerton ZH, Chavez J, D'Amico AV, Feng FY, Rebbeck TR, et al: Prostate cancer incidence across stage, NCCN risk groups, and age before and after USPSTF Grade D recommendations against prostate-specific antigen screening in 2012. Cancer. 126:717–724. 2020.PubMed/NCBI View Article : Google Scholar
78	Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R and Jemal A: Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 66:271–289. 2016.PubMed/NCBI View Article : Google Scholar
79	McCrea E, Sissung TM, Price DK, Chau CH and Figg WD: Androgen receptor variation affects prostate cancer progression and drug resistance. Pharmacol Res. 114:152–162. 2016.PubMed/NCBI View Article : Google Scholar
80	Zhang Y, Duan H, Zhao H, Qi L, Liu Y, Zhang Z, Liu C, Chen L, Jin M, Guan Y, et al: Development and evaluation of a PSMA-targeted nanosystem co-packaging docetaxel and androgen receptor siRNA for castration-resistant prostate cancer treatment. Pharmaceutics. 14(964)2022.PubMed/NCBI View Article : Google Scholar
81	Zhao Y, Li J, Chen J, Ye M and Jin X: Functional roles of E3 ubiquitin ligases in prostate cancer. J Mol Med (Berl). 100:1125–1144. 2022.PubMed/NCBI View Article : Google Scholar
82	Li H, Xu LL, Masuda K, Raymundo E, McLeod DG, Dobi A and Srivastava S: A feedback loop between the androgen receptor and a NEDD4-binding protein, PMEPA1, in prostate cancer cells. J Biol Chem. 283:28988–28995. 2008.PubMed/NCBI View Article : Google Scholar
83	Zhang J, Xie JJ, Zhou SJ, Chen J, Hu Q, Pu JX and Lu JL: Diosgenin inhibits the expression of NEDD4 in prostate cancer cells. Am J Transl Res. 11:3461–3471. 2019.PubMed/NCBI
84	Kim SE, Paik HY, Yoon H, Lee JE, Kim N and Sung MK: Sex- and gender-specific disparities in colorectal cancer risk. World J Gastroenterol. 21:5167–5175. 2015.PubMed/NCBI View Article : Google Scholar
85	Xi Y and Xu P: Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 14(101174)2021.PubMed/NCBI View Article : Google Scholar
86	Rattray NJW, Charkoftaki G, Rattray Z, Hansen JE, Vasiliou V and Johnson CH: Environmental influences in the etiology of colorectal cancer: The premise of metabolomics. Curr Pharmacol Rep. 3:114–125. 2017.PubMed/NCBI View Article : Google Scholar
87	Parmar S and Easwaran H: Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf). 10(goac035)2022.PubMed/NCBI View Article : Google Scholar
88	Hsieh MH, Kung PT, Kuo WY, Ke TW and Tsai WC: Recurrence, death risk, and related factors in patients with stage 0 colorectal cancer: A nationwide population-based study. Medicine (Baltimore). 99(e21688)2020.PubMed/NCBI View Article : Google Scholar
89	Mishra J, Drummond J, Quazi SH, Karanki SS, Shaw JJ, Chen B and Kumar N: Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. Crit Rev Oncol Hematol. 86:232–250. 2013.PubMed/NCBI View Article : Google Scholar
90	Golshani G and Zhang Y: Advances in immunotherapy for colorectal cancer: A review. Therap Adv Gastroenterol. 13(1756284820917527)2020.PubMed/NCBI View Article : Google Scholar
91	Eide PW, Cekaite L, Danielsen SA, Eilertsen IA, Kjenseth A, Fykerud TA, Ågesen TH, Bruun J, Rivedal E, Lothe RA and Leithe E: NEDD4 is overexpressed in colorectal cancer and promotes colonic cell growth independently of the PI3K/PTEN/AKT pathway. Cell Signal. 25:12–18. 2013.PubMed/NCBI View Article : Google Scholar
92	Aikemu B, Shao Y, Yang G, Ma J, Zhang S, Yang X, Hong H, Yesseyeva G, Huang L, Jia H, et al: NDRG1 regulates Filopodia-induced Colorectal Cancer invasiveness via modulating CDC42 activity. Int J Biol Sci. 17:1716–1730. 2021.PubMed/NCBI View Article : Google Scholar
93	Zou X, Levy-Cohen G and Blank M: Molecular functions of NEDD4 E3 ubiquitin ligases in cancer. Biochim Biophys Acta. 1856:91–106. 2015.PubMed/NCBI View Article : Google Scholar
94	Zhang S, Yu C, Yang X, Hong H, Lu J, Hu W, Hao X, Li S, Aikemu B, Yang G, et al: N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21. J Exp Clin Cancer Res. 38(490)2019.PubMed/NCBI View Article : Google Scholar
95	Lu C, Thoeni C, Connor A, Kawabe H, Gallinger S and Rotin D: Intestinal knockout of Nedd4 enhances growth of Apc^min tumors. Oncogene. 35:5839–5849. 2016.PubMed/NCBI View Article : Google Scholar
96	Tanksley JP, Chen X and Coffey RJ: NEDD4L is downregulated in colorectal cancer and inhibits canonical WNT signaling. PLoS One. 8(e81514)2013.PubMed/NCBI View Article : Google Scholar
97	Liu J, Shaik S, Dai X, Wu Q, Zhou X, Wang Z and Wei W: Targeting the ubiquitin pathway for cancer treatment. Biochim Biophys Acta. 1855:50–60. 2015.PubMed/NCBI View Article : Google Scholar
98	Wang K, Yu Y, Wang W, Jiang Y, Li Y, Jiang X, Qiao Y, Chen L, Zhao X, Liu J, et al: Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer. Oncogene. 42:1072–1087. 2023.PubMed/NCBI View Article : Google Scholar
99	Ahn Y, Hwang CY, Lee SR, Kwon KS and Lee C: The tumour suppressor PTEN mediates a negative regulation of the E3 ubiquitin-protein ligase Nedd4. Biochem J. 412:331–338. 2008.PubMed/NCBI View Article : Google Scholar
100	Ao N, Chen Q and Liu G: The small molecules targeting ubiquitin-proteasome system for cancer therapy. Comb Chem High Throughput Screen. 20:403–413. 2017.PubMed/NCBI View Article : Google Scholar
101	Wang X, Duan J, Fu W, Yin Z, Sheng J, Lei Z and Wang H: Decreased expression of NEDD4L contributes to NSCLC progression and metastasis. Biochem Biophys Res Commun. 513:398–404. 2019.PubMed/NCBI View Article : Google Scholar
102	Yue M, Yun Z, Li S, Yan G and Kang Z: NEDD4 triggers FOXA1 ubiquitination and promotes colon cancer progression under microRNA-340-5p suppression and ATF1 upregulation. RNA Biol. 18:1981–1995. 2021.PubMed/NCBI View Article : Google Scholar
103	Kim SS, Yoo NJ, Jeong EG, Kim MS and Lee SH: Expression of NEDD4-1, a PTEN regulator, in gastric and colorectal carcinomas. APMIS. 116:779–784. 2008.PubMed/NCBI View Article : Google Scholar