The phospholipase C (PLC) family plays a crucial role in the construction of biomembranes, cell growth, and signal transduction. PLC regulates multiple cellular processes by generating bioactive molecules such as inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These products propagate and regulate cellular signaling via calcium (Ca2+) mobilization and activation of protein kinase C (PKC), other kinases, and ion channels. Recently, the function of PLC delta 3 (PLCδ3) has been arousing great interests in the basic research of neoplastic diseases. It is demonstrated to affect multiple parts of tumor progression and promote glycolysis reprogramming. However, currently there are no conclusive reports regarding the mechanism of PLCδ3-mediated tumor progression and its importance as a prognostic biomarker in specific neoplastic diseases. Therefore, the present article aimed to illustrate (1) the correlation between the function of phospholipases in PLC family and tumor progression; (2) the PLCδ3-mediated tumor progression, mainly focusing on the signal transduction and regulation; and (3) its potential mechanism and vital targets involved in multiple malignancies.
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References
1.
AnanthanarayananB, DasS, RheeSG, et al.Membrane targeting of C2 domains of phospholipase C-Delta isoforms. J Biol Chem, 2002; 277(5):3568–3575; doi: 10.1074/jbc.M109705200
2.
ArimuraN, KaibuchiK. Neuronal polarity: From extracellular signals to intracellular mechanisms. Nat Rev Neurosci, 2007; 8(3):194–205; doi: 10.1038/nrn2056
3.
ArmaniousH, AdamB, MeunierD, et al.Digital gene expression analysis might aid in the diagnosis of thyroid cancer. Curr Oncol, 2020; 27(2):e93–e99; doi: 10.3747/co.27.5533
4.
BunneyTD, KampyliC, GregoryA, et al.Characterisation of molecular mechanisms for PLCγ2 disease-linked variants. Adv Biol Regul, 2024; 94:101053; doi: 10.1016/j.jbior.2024.101053
5.
DavisFM, StewartTA, ThompsonEW, et al.Targeting EMT in cancer: Opportunities for pharmacological intervention. Trends Pharmacol Sci, 2014; 35(9):479–488; doi: 10.1016/j.tips.2014.06.006
6.
De MirandaMC, RodriguesMA, De Angelis CamposAC, et al.Epidermal growth factor (EGF) triggers nuclear calcium signaling through the intranuclear phospholipase Cδ-4 (PLCδ4). J Biol Chem, 2019; 294(45):16650–16662; doi: 10.1074/jbc.RA118.006961
7.
DerkaczewM, MartyniukP, HofmanR, et al.The genetic background of abnormalities in metabolic pathways of phosphoinositides and their linkage with the myotubular myopathies, neurodegenerative disorders, and carcinogenesis. Biomolecules, 2023; 13(10):1550; doi: 10.3390/biom13101550
8.
DouX-L, XiaF-D, LiX-Y. Circ_0003747 promotes thyroid cancer progression by sponging miR-338-3p to upregulate PLCD3 expression. Ciba F Symp, 2023; 18(1):2210339; doi: 10.1080/15592294.2023.2210339
9.
FanY, HaoY, ZhuC, et al.PLCε promotes the Warburg effect and tumorigenesis through AKT/GSK3β/Cdc25a in bladder cancer. Biotechnol Genet Eng Rev, 2024; 40(3):2155–2169; doi: 10.1080/02648725.2023.2199188
10.
FuL, QinY-R, XieD, et al.Characterization of a novel tumor-suppressor gene PLC Delta 1 at 3p22 in esophageal squamous cell carcinoma. Cancer Res, 2007; 67(22):10720–10726; doi: 10.1158/0008-5472.CAN-07-2411
11.
Ganapathy-KanniappanS, GeschwindJ-FH. Tumor glycolysis as a target for cancer therapy: Progress and prospects. Mol Cancer, 2013; 12(1):152; doi: 10.1186/1476-4598-12-152
12.
GressetA, SondekJ, HardenTK. The phospholipase C isozymes and their regulation. Subcell Biochem, 2012; 58:61–94; doi: 10.1007/978-94-007-3012-0_3
13.
Haas-KoganD, ShalevN, WongM, et al.Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol, 1998; 8(21):1195–1198; doi: 10.1016/s0960-9822(07)00493-9
14.
HanY, YuX, YinY, et al.Identification of potential BRAF inhibitor joint therapy targets in PTC based on WGCAN and DCGA. J Cancer, 2021; 12(6):1779–1791; doi: 10.7150/jca.51551
15.
HanahanD, WeinbergRA. Hallmarks of cancer: The next generation. Cell, 2011; 144(5):646–674; doi: 10.1016/j.cell.2011.02.013
16.
HuH, YinY, JiangB, et al.Cuproptosis signature and PLCD3 predicts immune infiltration and drug responses in osteosarcoma. Front Oncol, 2023; 13:1156455; doi: 10.3389/fonc.2023.1156455
17.
HuangB, LangX, LiX. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol, 2022; 12:1023177; doi: 10.3389/fonc.2022.1023177
18.
HuangY, QuS, ZhuG, et al.BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment. J Natl Cancer Inst, 2018; 110(4):362–370; doi: 10.1093/jnci/djx227
19.
JangH-J, SuhP-G, LeeYJ, et al.PLCγ1: Potential arbitrator of cancer progression. Adv Biol Regul, 2018; 67:179–189; doi: 10.1016/j.jbior.2017.11.003
20.
JangH-J, YangYR, KimJK, et al.Phospholipase C-γ1 involved in brain disorders. Adv Biol Regul, 2013; 53(1):51–62; doi: 10.1016/j.jbior.2012.09.008
21.
KimY-M, KimY-M, LeeYM, et al.TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. J Biol Chem, 2002; 277(9):6799–6805; doi: 10.1074/jbc.M109434200
22.
KimJ-M, ParkJ, NohE-M, et al.Bruton’s agammaglobulinemia tyrosine kinase (Btk) regulates TPA-induced breast cancer cell invasion via PLCγ2/PKCβ/NF-κB/AP-1-dependent matrix metalloproteinase-9 activation. Oncol Rep, 2021; 45(5):56; doi: 10.3892/or.2021.8007
23.
KouchiZ, IgarashiT, ShibayamaN, et al.Phospholipase Cδ3 regulates RhoA/Rho kinase signaling and neurite outgrowth. J Biol Chem, 2011; 286(10):8459–8471; doi: 10.1074/jbc.M110.171223
24.
KrauzeAV, ZhaoY, LiM-C, et al.Revisiting concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma-proteomic alteration and comparison analysis with the standard-of-care chemoirradiation. Biomolecules, 2023; 13(10):1499; doi: 10.3390/biom13101499
25.
LiM, EdamatsuH, KitazawaR, et al.Phospholipase cepsilon promotes intestinal tumorigenesis of Apc(Min/+) mice through augmentation of inflammation and angiogenesis. Carcinogenesis, 2009; 30(8):1424–1432; doi: 10.1093/carcin/bgp125
26.
LiangS, GuoH, MaK, et al.A PLCB1–PI3K–AKT signaling axis activates EMT to promote cholangiocarcinoma progression. Cancer Res, 2021; 81(23):5889–5903; doi: 10.1158/0008-5472.CAN-21-1538
27.
LinL, WenJ, LinB, et al.Phospholipase C delta 3 inhibits apoptosis and promotes proliferation, migration, and invasion of thyroid cancer cells via Hippo pathway. Acta Biochim Biophys Sin (Shanghai), 2021; 53(4):481–491; doi: 10.1093/abbs/gmab016
28.
LiuW, LiuX, WangL, et al.PLCD3, a Flotillin2-interacting protein, is involved in proliferation, migration and invasion of nasopharyngeal carcinoma cells. Oncol Rep, 2018; 39(1):45–52; doi: 10.3892/or.2017.6080
29.
LiuT-M, WoyachJA, ZhongY, et al.Hypermorphic mutation of phospholipase C, Γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood, 2015; 126(1):61–68; doi: 10.1182/blood-2015-02-626846
30.
LiuZ, WuX, WangQ, et al.CD73-Adenosine A1R axis regulates the activation and apoptosis of hepatic stellate cells through the PLC-IP3-Ca2+/DAG-PKC signaling pathway. Front Pharmacol, 2022; 13:922885; doi: 10.3389/fphar.2022.922885
31.
Lo VascoVR, LeopizziM, Della RoccaC. Ezrin-related phosphoinositide pathway modifies RhoA and Rac1 in human osteosarcoma cell lines. J Cell Commun Signal, 2015; 9(1):55–62; doi: 10.1007/s12079-015-0265-y
32.
LomasneyJW, ChengH-F, RofflerSR, et al.Activation of phospholipase C delta1 through C2 domain by a Ca(2+)-enzyme-phosphatidylserine ternary complex. J Biol Chem, 1999; 274(31):21995–22001; doi: 10.1074/jbc.274.31.21995
33.
MaK, WangS, MaY, et al.Increased oxygen stimulation promotes chemoresistance and phenotype shifting through PLCB1 in gliomas. Drug Resist Updat, 2024; 76:101113; doi: 10.1016/j.drup.2024.101113
34.
Mengie AyeleT, Tilahun MucheZ, Behaile TeklemariamA, et al.Role of JAK2/STAT3 signaling pathway in the tumorigenesis, chemotherapy resistance, and treatment of solid tumors: A systemic review. J Inflamm Res, 2022; 15:1349–1364; doi: 10.2147/JIR.S353489
35.
MuH, WangN, ZhaoL, et al.Methylation of PLCD1 and adenovirus-mediated PLCD1 overexpression elicits a gene therapy effect on human breast cancer. Exp Cell Res, 2015; 332(2):179–189; doi: 10.1016/j.yexcr.2015.01.017
36.
PakO, ZaitsevS, ShevchenkoV, et al.Effectiveness of bortezomib and temozolomide for eradication of recurrent human glioblastoma cells, resistant to radiation. Prog Brain Res, 2021; 266:195–209; doi: 10.1016/bs.pbr.2021.06.010
37.
ParkJB, LeeCS, JangJ-H, et al.Phospholipase signalling networks in cancer. Nat Rev Cancer, 2012; 12(11):782–792; doi: 10.1038/nrc3379
38.
PastushenkoI, BlanpainC. EMT transition states during tumor progression and metastasis. Trends Cell Biol, 2019; 29(3):212–226; doi: 10.1016/j.tcb.2018.12.001
39.
PawelczykT, MateckiA. Localization of phospholipase C Δ3 in the cell and regulation of its activity by phospholipids and calcium. Eur J Biochem, 1998; 257(1):169–177; doi: 10.1046/j.1432-1327.1998.2570169.x
40.
QuanZ, LiT, XiaY, et al.PLCɛ maintains the functionality of AR signaling in prostate cancer via an autophagy-dependent mechanism. Cell Death Dis, 2020; 11(8):716; doi: 10.1038/s41419-020-02917-9
41.
LiuR, BishopJ, ZhuG, et al.Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer: Genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality. JAMA Oncology, 2017; 3(2); doi: 10.1001/jamaoncol.2016.3288
42.
RebecchiMJ, RaghubirA, ScarlataS, et al.Expression and function of phospholipase C in breast carcinoma. Adv Enzyme Regul, 2009; 49(1):59–73; doi: 10.1016/j.advenzreg.2009.01.009
43.
RheeSG. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem, 2001; 70(1):281–312; doi: 10.1146/annurev.biochem.70.1.281
44.
SalaG, DituriF, RaimondiC, et al.Phospholipase cgamma1 is required for metastasis development and progression. Cancer Res, 2008; 68(24):10187–10196; doi: 10.1158/0008-5472.CAN-08-1181
ShimozawaM, AnzaiS, SatowR, et al.Phospholipase C δ1 negatively regulates autophagy in colorectal cancer cells. Biochem Biophys Res Commun, 2017; 488(4):578–583; doi: 10.1016/j.bbrc.2017.05.098
47.
ShuY, LanJ, LuoH, et al.FOS-mediated PLCB1 induces radioresistance and weakens the antitumor effects of CD8+ T cells in triple-negative breast cancer. Mol Carcinog, 2025; 64(1):162–175; doi: 10.1002/mc.23834
48.
SuhP-G, ParkJ-I, ManzoliL, et al.Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep, 2008; 41(6):415–434; doi: 10.5483/bmbrep.2008.41.6.415
49.
TyutyunnykovaA, TelegeevG, DubrovskaA. The controversial role of phospholipase C epsilon (PLCε) in cancer development and progression. J Cancer, 2017; 8(5):716–729; doi: 10.7150/jca.17779
50.
WangX, FanY, DuZ, et al.Knockdown of phospholipase Cε (PLCε) inhibits cell proliferation via phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/AKT signaling pathway in human prostate cancer. Med Sci Monit, 2018; 24:254–263; doi: 10.12659/msm.908109
51.
WangM, GaoM, ChenY, et al.PLCD3 promotes malignant cell behaviors in esophageal squamous cell carcinoma via the PI3K/AKT/P21 signaling. BMC Cancer, 2023; 23(1):921; doi: 10.1186/s12885-023-11409-w
52.
WenX, ZhangB, WuB, et al.Signaling pathways in obesity: Mechanisms and therapeutic interventions. Signal Transduct Target Ther, 2022; 7(1):298; doi: 10.1038/s41392-022-01149-x
53.
WuM, MuC, YangH, et al.8-Br-cGMP suppresses tumor progression through EGFR/PLC Γ1 pathway in epithelial ovarian cancer. Mol Biol Rep, 2024; 51(1):140; doi: 10.1007/s11033-023-09037-5
54.
WuY-N, SuX, WangX-Q, et al.The roles of phospholipase C-β related signals in the proliferation, metastasis and angiogenesis of malignant tumors, and the corresponding protective measures. Front Oncol, 2023; 13:1231875; doi: 10.3389/fonc.2023.1231875
55.
XieJ, ZhouJ, XiaJ, et al.Phospholipase C delta 1 inhibits WNT/β-Catenin and EGFR-FAK-ERK signaling and is disrupted by promoter CpG methylation in renal cell carcinoma. Clin Epigenetics, 2023; 15(1):30; doi: 10.1186/s13148-023-01448-2
56.
YuY, BaralS, SunQ, et al.PLCD3 inhibits apoptosis and promotes proliferation, invasion and migration in gastric cancer. Discov Oncol, 2024; 15(1):26; doi: 10.1007/s12672-024-00881-w
57.
ZającA, Sumorek-WiadroJ, MaciejczykA, et al.The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction. Neuropharmacology, 2025; 262:110204; doi: 10.1016/j.neuropharm.2024.110204
58.
ZhangL, LiM, LiX, et al.Deciphering the role of PLCD3 in lung cancer: A gateway to glycolytic reprogramming via PKC-Rap1 activation. Heliyon, 2024; 10(17):e37063; doi: 10.1016/j.heliyon.2024.e37063
59.
ZhangH, XieT, ShuiY, et al.Knockdown of PLCB2 expression reduces melanoma cell viability and promotes melanoma cell apoptosis by altering Ras/Raf/MAPK Signals. Mol Med Rep, 2020; 21(1):420–428; doi: 10.3892/mmr.2019.10798
60.
ZhouX, LiaoX, WangX, et al.Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms. Cancer Med, 2020; 9(3):859–871; doi: 10.1002/cam4.2699
61.
ZhuZ-J, QiZ, ZhangJ, et al.Untargeted metabolomics analysis of esophageal squamous cell carcinoma discovers dysregulated metabolic pathways and potential diagnostic biomarkers. J Cancer, 2020; 11(13):3944–3954; doi: 10.7150/jca.41733
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