Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Telomeres, Telomerase, and TERT
3. Telomerase and Cancer
Gene (Animal) | Site Specificity | Expression * | Result ** | Ref. |
---|---|---|---|---|
Tert (mouse) | Thymocytes and peripheral T cells | + | ↑ T-Cell Lymphomas | [16] |
Tert (mouse) | Basal keratinocytes | + | ↑ skin papillomas (DMBA + TPA induction) | [17] |
Tert (mouse) | Whole body | + | ↑ mammary tumors in aged females | [18] |
tert and terc (zebrafish) | Neural progenitor cells | + | ↓ aggressiveness of RAS-mediated brain tumors | [27] |
Tert (mouse) | Whole body | − | Delayed onset of lymphomas in EμMYC mice | [20] |
Tert (mouse) | Whole body | − | Delayed onset of mammary tumors in PyMT mice | [19] |
Tert (mouse) | Whole body | − | ↓ HCC “initiation foci” (CCl4 induction) | [21] |
Terc (mouse) | Whole body | − | ↑ HCC “initiation foci” but ↓ HCC progression (uPA, CCl4 or DEN induction) | [22] |
Terc (mouse) | Whole body | − | ↑ tumors (lymphomas, teratocarcinomas, HCC, squamous cell carcinoma) | [26] |
Terc (mouse) | Whole body | − | ↓ skin papillomas (DMBA + TPA induction) | [28] |
Terc (mouse) | Whole body | − | ↑ epithelial cancers in TP53−/− mice | [29] |
Terc (mouse) | Whole body | − | ↑ adenoma initiation but ↓ progression in ApcMin mice | [30] |
terthu3430 (zebrafish) | Whole body | − | Earlier onset of tumors (germ cell tumors, hematopoietic neoplasms, HCA, etc.) | [23] |
terthu3430 (zebrafish) | Whole body | − | ↑ tumor incidence and aggressiveness of melanoma model *** | [31] |
4. TERT Promoter Mutations in HCC
Region | Etiology (N) | C228T Incidence % (N) | C250T Incidence % (N) | Association * | Ref. |
---|---|---|---|---|---|
(1) Asia (2) Africa (3) Europe | 52.3% HBV, rest unknown (regions 1–3) (44) | (1) 16% (3) (2) 33% (5) (3) 20% (2) | (1) 5% (1) (2) 20% (3) (3) 10% (1) | ↑ frequency in Africans vs. non-Africans (p = 0.056) and in HBV− vs. HBV+ (p = 0.295) (regions 1–3) | [48] |
Southern Italy | (67) | 41.8% (28) | 0% (0) | ↑ TERT expression in mutated tumors vs. control tissue (p < 0.0001) | [41] |
Southern Italy | 7.9% HBV+, 86.6% HCV+ (127) | 48.8% (62) | 1.6% (2) | ↑ frequency in HCV+ vs. HBV+ (p < 0.001) | [43] |
Germany | (78) | 47.4% (37) | [49] | ||
France, Italy and Spain | 14% HBV+, 26% HCV+ (243) | 54.3% (132) | 2% (5) | [6] | |
France | 22% HBV+, 26% HCV+ (305) | 55% (168) | 3.6% (11) | ↑ frequency in males vs. females (p = 0.001) and in HBV− vs. HBV+ (p < 0.0001); ↑ TERT expression in mutated HCC vs. normal liver, cirrhosis, and HCA (p = 0.0007) | [5] |
USA | 24.6% HBV+, 26% HCV+ (61) | 42.6% (26) | 1.6% (1) | no correlation with etiology, sex, age, or ethnicity | [50] |
(1) USA (2) Japan | (1) 14.6% HBV+, 57% HCV+ (89) (2) 28.6% HBV+, 37% HCV+ (374) | (1) 34.8% (31) (2) 55.6% (208) | (1) 2.2% (2) (2) 2.4% (9) | ↑ frequency in HCV+ vs. HCV− (p = 0.0016) | [7,42] |
China | 94% HBV+ (276) | 30.5% (84) | 0.36% (1) | ↑ frequency in older vs. younger age (p = 0.04); no correlation with sex or etiology | [51] |
China | (35) | 25.7% (9) | 5.7% (2) | [52] | |
China | 83% HBV+ (190) | 26.3% (50) | 3.7% (7) | no correlation with age, sex, etiology, or tumor status | [53] |
Japan | (11) | 81.8% (9) | [54] | ||
Japan | 23% HBV+, 61.6% HCV+ (125) | 66.4% (83) | 1.6% (2) | ↑ frequency in HCV+ vs. HCV− (p = 0.0007) and in viral vs. non-viral (p = 0.0282) | [45] |
South Korea | 36% HBV+, 3% HCV+ (160) | 20% (32) | 8.75% (14) | ↑ frequency in males vs. females (p = 0.027) and in HCV+ vs. HCV− (p = 0.285); no association with telomere length or HCC prognosis | [35] |
South Korea | 74% HBV+, 5.7% HCV+ (105) | 37% (39) | 1.9% (2) | ↑ frequency in HCV+ vs. HCV− (p = 0.001) | [46] |
Taiwan | 63% HBV+, 40.2% HCV+ (195) | 27.7% (54) | 1.5% (3) | ↑ frequency in HCV+ vs. HCV− (p = 0.0048), older vs. younger age (p = 0.0122), and HBV− vs. HBV+ (p = 0.0007) | [34] |
USA, Canada, South Korea, Vietnam, and Russia | 22.4% HBV+, 17.8% HCV+ (196) | 40.8% (80) | 3.6% (7) | ↑ frequency in older vs. younger age (p = 0.0006), males vs. females (p = 0.006), HCV+ vs. HCV− (p = 0.04), and HBV− vs. HBV+ (p = 0.02); no association with TERT expression | [44] |
5. WNT/β-Catenin Signaling in Normal and Cancer Cells
6. WNT/β-Catenin in HCC
Animal | Method * | Expression ** | CTNNB1 Status *** | Results | Ref. |
---|---|---|---|---|---|
Mice | Alb promoter | + | Wildtype | Transgenic mice develop hepatomegaly but no tumors | [71] |
Alb promoter | + | Ser45 mutated | Transgenic mice develop hepatomegaly (only in younger mice) but no tumors; Increased HCC (DEN induction) | [72] | |
Fabp: Cre | + | Exon 3 deleted | Transgenic mice develop hepatomegaly but no tumors | [73] | |
CaBP9K promoter | + | N131 deleted | Transgenic mice develop hepatomegaly but no tumors | [74] | |
Cited1: CreER | + | Exon 3 deleted | Transgenic mice develop HCCs, hepatoblastomas, and lung metastases | [79] | |
AdCMV-Cre | + | Exon 3 deleted (and H-RAS) | Double transgenic mice develop HCC, but no HCC develops with expression of mutated CTNNB1 alone | [78] | |
SB-HDT | + | S45 or S33 mutated (and MET) | Mice expressing MET and either form of mutated CTNNB1, but not mutated CTNNB1 alone, develop HCC | [75] | |
SB-HDT | + | N90 deleted (and activated YAP) | Mice expressing activated YAP and mutated CTNNB1, but not mutated CTNNB1 alone, develop HCC | [76] | |
SB-HDT | + | S45 or S33 mutated (and K-RAS) | Mice expressing K-RAS and either form of mutated CTNNB1, but not mutated CTNNB1 alone, develop HCC | [77] | |
siRNA | − | S45 mutated (HDT induction) | Decreased HCC (K-RAS plus S45-mutated CTNNB1 HDT induction) | [77] | |
Alb:Cre | − | Wildtype (endogenous) | Increased HCC (DEN induction) | [82] | |
Alb:Cre | − | Wildtype (endogenous) | Increased HCC (MET and N90-deleted CTNNB1 induction) | [83] | |
Zebrafish | fabp10a promoter | + | S33A, S37A, T41A, and S45A mutated | Transgenic zebrafish develop HCC as adults (78% by 6 months) | [81] |
fabp: CreERT2 | + | Transgenic zebrafish develop HCC as adults (13% by 6 months) | [80] |
7. Interactions between TERT and β-Catenin in Cultured Cells and Animal Models
8. TERT and β-Catenin in Human Cancer
9. TERT and β-Catenin in HCC Patients
10. TERT and β-Catenin in Vertebrate HCC Models
11. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Region | Etiology (N) | TERTp % Incidence (N) | CTNNB1 % Incidence (N) | Association | Ref. |
---|---|---|---|---|---|
France | 22% HBV+, 26% HCV+ (305) | 59% (179) | 33% (101) | Significant, p < 0.0001 | [5] |
France | 20.7% HBV+, 26.5% HCV+ (801) | 58.1% (441) | 30.7% (229) | Significant, p = 0.0000001 | [103] |
Southern Italy | 7.9% HBV+, 86.6% HCV+ (127) | 50.4% (64) | 26% (33) | Not significant, p = 0.4192 | [43] |
USA and Japan | 25.6% HBV+, 42.6% HCV+ (469) | 54.1% (254) | 31.1% (146) | Significant, p < 0.0001 | [7] |
Japan | NAFLD (11) | 82% (9) | 45% (5) | Not significant, p = 0.4545 | [54] |
Taiwan | 63% HBV+, 40.2% HCV+ (195) | 29.2% (57) | 16.5% (31/188) | Not significant, p = 0.2055 | [34] |
Korea | 74.3% HBV+, 5.7% HCV+; (105) | 39% (41) | 14.6% (15) | Not significant, p = 0.568 | [46] |
China | 83% HBV+ (190) | 30% (57) | 24.3% (17/70) | Not significant, p = 0.535 | [53] |
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Kotiyal, S.; Evason, K.J. Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma. Cancers 2021, 13, 4202. https://doi.org/10.3390/cancers13164202
Kotiyal S, Evason KJ. Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma. Cancers. 2021; 13(16):4202. https://doi.org/10.3390/cancers13164202
Chicago/Turabian StyleKotiyal, Srishti, and Kimberley Jane Evason. 2021. "Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma" Cancers 13, no. 16: 4202. https://doi.org/10.3390/cancers13164202