The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects
Abstract
:1. Introduction
2. TTP Family Proteins and Cell Cycle Control
3. TTP Family Proteins and Control of Apoptosis
4. TTP Family Proteins and Regulation of Pro-Tumorigenic Inflammatory Mediators
5. TTP Family Proteins and Cellular Senescence
6. TTP Family Proteins and Regulation of Angiogenesis
7. TTP Family Proteins and Epithelial Mesenchymal Transition
8. TTP Family Proteins and Tumor Suppressor and Oncogenic Roles
9. TTP Family Proteins and Regulation of Tumor Metastasis
10. TTP Family Proteins as Potential Biomarkers
11. TTP Family Proteins and Response to Treatment
12. Outstanding Questions
13. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
3′UTR | 3′-untranslated region |
AHRR | aryl hydrocarbon receptor-repressor |
ARES | au-rich elements |
BCL2 | B-cell lymphoma-2 |
BERG36 | 36-Kda Zinc finger protein |
BRF | Butyrate response factor |
C-MYC | Myc protooncogene |
CDK6 | cyclin-dependent kinase 6 |
CIAP2 | cellular inhibitors of apoptosis 2 |
COX2 | cyclooxygenase 2 |
CXCL8 | chemokine (c-x-c motif) ligand 8 |
E2F1 | E2F transcription factor 1 |
EMT | epithelial-mesenchymal transition |
ERA | estrogen receptor alpha |
ERF | EGF-response factor 1 |
GALR2 | galanin receptor type 2 |
GOS24 | G0/G1 switch regulatory protein 24 |
HBV | hepatitis b virus |
HIF-1A | hypoxia-inducible factor 1 alpha |
hTERT | human telomerase reverse transcription gene |
IL-13 | interleukin 13 |
IL-23 | interleukin 23 |
IL-27 | interleukin 27 |
IL-3 | interleukin 3 |
IL-33 | interleukin 33 |
IL-6 | interleukin 6 |
IL-8 | interleukin 8 |
LATS2 | large tumor suppressor kinase 2 |
MACC1 | metastasis-associated in colon cancer 1 |
MMP1 | matrix metalloproteinase 1 |
MMP2 | matrix metalloproteinase 2 |
MMP9 | matrix metalloproteinase 9 |
mTOR | mammalian target of rapamycin |
NEDD9 | neural precursor cell expressed developmentally downregulated protein 9 |
NF-KB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NME1 | nucleoside diphosphate kinase 1 |
NUP475 | growth factor-inducible nuclear protein nup475 |
PD-L1 | programmed death-ligand 1 |
PI3K | phosphatidylinositol-3-kinase |
PIM1 | proto-oncogene serine/threonine-protein kinase 1 |
PIM2 | proto-oncogene serine/threonine-protein kinase 2 |
RB | retinoblastoma 1 |
SASP | senescence associated secretory protein |
SNAI1 | zinc finger protein snail 1 |
SOX9 | sry-box transcription factor 9 |
TGF-B1 | transforming growth factor beta 1 |
TIS11 | tpa-inducible sequence 11 |
TNFA | tumor necrosis factor alpha |
TTP | tristetraprolin |
TWIST1 | twist-related protein 1 |
UPA | urokinase-type plasminogen activator |
UPAR | urokinase plasminogen activator receptor |
VEGF | vascular endothelial growth factor |
XIAP | x-linked inhibitor of apoptosis |
ZEB1 | zinc finger e-box binding homeobox 1 |
ZEB2 | zinc finger e-box binding homeobox 2 |
ZFP36 | zinc finger protein 36 |
ZFP36L1 | zinc finger protein 36 like 1 |
ZFP36L2 | zinc finger protein 36 like 2 |
ZFP36L3 | zinc finger protein 36 like 3 |
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Gene Name | Protein Names | Ref-Seq mRNA | Ref-Seq Protein | Amino Acids |
---|---|---|---|---|
ZFP36 | TTP, TIS11, GOS24, NUP475 | NM_003407 | NP_003398 | 332 |
ZFP36L1 | TIS11b, cMG1, BRF1, ERF1, Berg36, | NM_004926 | NP_004917 | 407 |
ZFP36L2 | TIS11d, BRF2, ERF2 | NM_006887 | NP_008818 | 497 |
Cancer Type/Cancer Cell Lines | TTP Family RBPs | Major Findings (References) | Targets |
---|---|---|---|
Bladder Cancer | TTP/ZFP36 | Bladder cancers express a TTP-low gene signature [19] | |
ZFP36L1 | ZFP36L1 targets cell-cycle and hypoxia regulators, CCND1, E2F1, and HIF1A in bladder cancer cells [15]. | CCND1, E2F1, HIF1A | |
ZFP36L2 | ZFP36L2, among other 7 genes, was identified as a prognostic indicator in muscle-invasive bladder cancer [20]. | ||
Breast Cancer | TTP/ZFP36 | TTP is significantly downregulated in invasive breast cancer cells; TTP directly targets uPA, uPAR, and MMP1 [21]. | uPA, uPAR, MMP1 |
TTP is downregulated in advanced breast and prostate cancers and is a negative prognostic indicator in breast cancer patients. Restoring TTP expression suppresses cell proliferation, resistance to apoptosis, and VEGF mRNA [16]. | VEGF | ||
TTP expression inversely correlates with breast cancer aggressiveness and metastatic potential. A synonymous polymorphism in TTP gene in Hs578T cells is significantly associated with lack of response to Herceptin in HER2-positive breast cancer patients [22]. | |||
TTP inhibits AHRR expression [23]. | AHRR | ||
TTP is significantly downregulated in invasive breast carcinomas. TTP expression positively correlates with differentiation in normal and tumor cells [17]. | |||
Low TTP-expressing breast cancer and lung adenocarcinoma patients show reduced survival and more aggressive tumors. The TTP-low gene signature is characterized by 20 underexpressed CREB targets [19]. | |||
TTP binds to ERα and represses ERα transactivation in breast cancer cells, resulting in reduced proliferation and reduced ability of cells to form tumors in a mouse model [24]. | |||
MicroRNA-29a overexpression suppresses TTP and promotes EMT and metastasis in breast cancer cells. miR-29a is upregulated and TTP is downregulated in breast cancer patient samples [25]. | |||
TTP inhibits c-Jun transcription by impairing NF-κB p65 nuclear translocation resulting in S-phase cell cycle arrest in breast cancer cells [26]. | |||
TTP suppresses mitosis by downregulating a cluster of mitosis ARE mRNAs. Poor breast cancer patient survival is significantly associated with low TTP and high mitotic ARE-mRNAs [27]. | |||
Metformin induces TTP expression in breast cancer cells in a Myc-dependent manner and impairs cell proliferation [28]. | |||
Macrophage TTP suppresses T-cell function by inhibiting IL-27 production, thus accelerating tumor growth [29]. | IL-27 | ||
ZFP36L1 | ZFP36L1, among others, was overexpressed in lymph node positive primary breast tumors [30]. | ||
Chemotherapy induced activation of p38 resulted in phosphorylation/inactivation of ZFP36L1 thus stabilizing Nanog and Klf4 mRNA that resulted in chemotherapy-resistant breast cancer stem cell phenotype [31]. | KLF4, NANOG | ||
ZFP36L1 is downregulated in human breast tumor samples and three breast cancer cell lines [32]. | |||
ZFP36L2 | Expression of ZFP36L2, among other genes, significantly associated with the development of bone metastasis in breast cancer [33]. | ||
Cervical Cancer | TTP/ZFP36 | TTP is downregulated in cervical cancer tissues. In HPV-positive HeLa cells, TTP induced cellular senescence by promoting decay of the cellular ubiquitin ligase E6-associated protein (E6-AP) [34]. | E6-AP |
Colon, Colorectal Cancer | TTP/ZFP36 | TTP binds and degrades COX-2 mRNA in human colorectal adenocarcinoma cells [11]. | COX-2 |
TTP binds and degrades IL-23 mRNA in mouse colon cancer cells [35]. | IL-23 | ||
Forced expression of TTP blocks EMT and induces anoikis. TTP expression impairs three key EMT transcription factors, ZEB1, MACC1 and SOX9 [36]. | ZEB1, MACC1, SOX9 | ||
TTP negatively regulates PD-L1 expression, an immunosuppressive protein that plays a role in evasion of the host immune system [37]. | PD-L1 | ||
Gambogic acid (GA) killed stem-like colorectal cancer cells by upregulating TTP [38]. | |||
Resveratrol suppressed the proliferation and invasion/metastasis of colorectal cancer cells by activating TTP [39]. | |||
Epithelial Ovarian Cancer | ZFP36L1 | ZFP36L1 was identified as mucinous-type epithelial ovarian cancer risk gene in a GWAS study [40]. | |
Esophageal Squamous cell Carcinoma | ZFP36L2 | ZFP36L2 was identified as a significantly mutated gene in esophageal squamous cell carcinoma and was validated as a tumor suppressor in this cancer type [41]. | |
Follicular Thyroid Carcinoma | ZFP36L2 | ZFP36L2 was identified as a metastasis suppressor, NME1 regulated gene in human follicular thyroid carcinoma cell lines [42]. | |
Gastric Cancer | TTP/ZFP36 | TTP is significantly reduced in gastric cancer tissues and is associated with invasion, lymph node metastasis, and survival. TTP suppresses IL-33 and inhibits the progression of gastric cancer [43]. | IL-33 |
ZFP36L2 | ZFP36L2 is upregulated in gastric cancer samples. Overexpressed ZFP36L2 in gastric epithelial cells promoted cell growth and colony formation. Silencing ZFP36L2 reduces NCI-N87 growth in vivo. A tandem duplication hotspot in the super-enhancer region of ZFP36L2 was associated with an increase in ZFP36L2 expression [44]. | ||
Glioblastoma Multiforme | TTP/ZFP36 | Ectopic TTP expression impairs the viability and invasiveness of glioblastoma cell lines. PIM-1, PIM-2, and XIAP are TTP targets [45]. | PIM-1, PIM-2, XIAP |
Glioma | TTP/ZFP36 | Hyperphosphorylation/inactivation of TTP by p38-MAPK promoted progression of malignant gliomas by inhibiting its RNA destabilizing function. Induced expression of TTP blocked glioma cell proliferation and survival through rapid decay of IL-8 and VEGF [46]. | IL-8, VEGF |
Resveratrol suppressed cell growth and induced apoptosis in human glioma cells by inducing TTP [47]. | |||
Retroviral oncoprotein Tax interacts with TTP and increases TNFα expression [48]. | |||
ZFP36L1 | ZFP36L1 is required for oligodendrocyte-astrocyte lineage transition and thus is an important regulator of gliomagenesis [49]. | ||
Leukemia | TTP/ZFP36 | Hydroquinone induces apoptosis in human leukemia cells through p38 MAPK-TTP phosphorylation/inactivation and resulting TNFα upregulation [50]. | TNFα |
Albendazole induces apoptosis in human leukemia cells through p38 MAPK-TTP phosphorylation/inactivation and resulting TNFα upregulation [51]. | TNFα | ||
ZFP36L1 | ZFP36L1 is downregulated in acute myeloid leukemia patient samples [52]. | NOTCH1 | |
Thymocyte-specific ZFP36L1 and ZFP36L2 deficient mice develop T cell acute lymphoblastic leukemia by upregulating Notch 1 [8]. | |||
Liver Cancer | TTP/ZFP36 | TTP was reduced in HCC cells and tissues. Methylation of a single CpG site within the TGF-beta1-responsive region of the TTP promoter was significantly associated with TTP downregulation in both HCC cells and tissues [53]. | |
TTP is downregulated in HCC tumors and hepatic TTP has a tumor suppressive role during tumor progression [54]. | |||
Lung Adenocarcinoma | TTP/ZFP36 | Patients with low-TTP expressing lung adenocarcinoma had decreased survival rates and more aggressive tumors [19]. | |
TTP is significantly downregulated in human lung tumor samples [37]. | |||
Lymphoma | TTP/ZFP36 | MYC suppresses TTP expression and TTP suppression is a hallmark of cancers with MYC involvement. Restoring TTP impairs Myc-induced lymphomagenesis [9]. | |
ZFP36L1 | ZFP36L1 mediates pro-apoptotic effects in malignant B-cells by promoting the decay of BCL-2 [10]. | BCL-2 | |
Hepatitis B virus associated diffuse large B-cell lymphoma patients have enrichment of genes regulated by ZFP36L1, among others [55]. | |||
Mast Cell Tumor | TTP/ZFP36 | Ectopic TTP expression delayed v-H-ras induced mast cell tumor progression by enhancing the degradation of IL-3 [56]. | IL-3 |
Melanoma | TTP/ZFP36 | Human melanoma cell lines express very low TTP. TTP regulates the expression of CXCL8 in melanoma cells [57]. | CXCL8 |
Anti-tumor activity of DM-1, a curcumin analogue in melanoma cells is potentially mediated by TTP, ZFP36L1, and ZFP36L2 among others [58]. | |||
ZFP36L2 | ZFP36L2 was identified as metastasis suppressor, NME1 regulated gene in human melanoma cell lines [42]. | ||
Myelofibrosis | ZFP36L1 | ZFP36L1 is a novel candidate tumor suppressor gene in myelofibrosis. Aberrant enhancer hypermethylation of ZFP36L1 reduced its expression in a myelofibrosis cohort [59]. | |
Pancreatic Cancer | TTP/ZFP36 | Pancreatic cancers express a TTP-low gene signature [19]. | |
miR-29a was up-regulated and TTP downregulated in pancreatic cancer tissues and cell lines. miR-29a overexpression correlated with increased metastasis. miR-29a enhanced the expression of pro-inflammatory and EMT markers by suppressing TTP [60]. | |||
TTP was markedly reduced in pancreatic cancer samples. Low TTP was associated with age, tumor size, tumor differentiation, post-operative T, N, and TNM stage. Low TTP predicted poor prognosis in pancreatic cancer patients. Over-expression of TTP in pancreatic cancer cells increased apoptosis, decreased cellular proliferation, and reduced expression of PIM-1 and IL-6 [61]. | PIM-1, IL-6 | ||
ZFP36L2 | ZFP36L2 was overexpressed and predicted poor patient outcomes in pancreatic ductal adenocarcinoma. ZFP36L2 was regulated by miR-375 in this cancer [62]. | ||
Prostate Cancer | TTP/ZFP36 | NEDD9 and ZFP36 were discovered as NF-κB regulators in prostate cancer. NEDD9 and TTP physically interact; knockdown of NEDD9 inhibited prostate cancer cellular proliferation [63]. | |
Low-TTP in prostate cancer correlated with increased recurrence. Induced TTP expression reduced cell proliferation, clonogenic growth, and tumorigenic potential of prostate cancer cells [64]. | |||
TTP protein was significantly lower in human prostate cancer tissues [65]. | |||
Low TTP levels in prostate cancer shorten time to recurrence or metastasis compared with TTP-high tumors [66]. | |||
Rectal Cancer | TTP/ZFP36 | TTP levels in the peripheral blood mononuclear cells were higher in patients with locally advanced rectal cancer that responded to chemoradiation [67]. | |
Squamous Cell Carcinoma of the Head and Neck (SCCHN) | TTP/ZFP36 | Downregulated TTP significantly increased invasion across the basement membrane via IL-6, MMP2, and MMP9 secretion in SCCHN oral-cancer-equivalent three-dimensional in vitro model and the chick chorioallantoic membrane in vivo assay [68]. | IL-6, MMP2, MMP9 |
Galanin receptor 2 induces angiogenesis in SCCHN through GALR2 ≥ RAP1B ≥ p38MAPK ≥ TTP phosphorylation/inactivation ≥ increased stability of IL-6 and VEGF mRNA, axis [69]. | IL-6, VEGF | ||
TTP increases cisplatin sensitivity of SCCHN cells by inhibiting anti-apoptotic protein BCL-2 [70]. | BCL-2 | ||
ZFP36L1 | Cisplatin sensitive head and neck squamous cell carcinoma cells have elevated levels of ZFP36L1. Elevated ZFP36L1 blocks cIAP2 and enhances caspase 3 activity [71]. | cIAP2 | |
Thyroid Cancer | ZFP36L2 | ZFP36L2 was identified as a part of gene-regulatory network involved in endodermal carcinogenesis and validated in cellular and mouse models of thyroid cancer [72]. |
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Saini, Y.; Chen, J.; Patial, S. The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects. Cancers 2020, 12, 1539. https://doi.org/10.3390/cancers12061539
Saini Y, Chen J, Patial S. The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects. Cancers. 2020; 12(6):1539. https://doi.org/10.3390/cancers12061539
Chicago/Turabian StyleSaini, Yogesh, Jian Chen, and Sonika Patial. 2020. "The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects" Cancers 12, no. 6: 1539. https://doi.org/10.3390/cancers12061539