©2023 PFPC
In 2022, Toma et al. set out to determine the effects of COVID-19 in patients with HCV-associated hepatocellular carcinoma (HCC) and thyroid comorbidities.
COVID-19
"At baseline, 44 patients had positive antithyroid antibodies, 6 had hypothyroidism in substitution and 2 had hyperthyroidism under treatment. During COVID-19 we found an increase in serum values of antithyroid antibodies, and decreased levels of TSH, freeT3 and freeT4 levels. Specific therapies were discontinued in one patient with hyperthyroidism and 3 patients with hypothyroidism." (Toma et al., 2022)
- Toma L, Zgura A, Isac T, Simu R, Mercan-Stanciu A, Dodot M, Iliescu EL - "Covid-19 and the thyroid function in patients with HCV-associated hepatocellular carcinoma" Avta Endocrinol 18(3):392-396 (2022) doi: 10.4183/aeb.2022.392
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867823/
FLUORIDE:
Kassahun WT, Günl B, Jonas S, Ungemach FR, Abraham G - "Altered liver α1-adrenoceptor density and phospholipase C activity in the human hepatocellular carcinoma" Eur J Pharmacol 670(1):92-5 (2011). doi: 10.1016/j.ejphar.2011.08.009. Epub 2011 Sep 2
https://pubmed.ncbi.nlm.nih.gov/21910987/
"NaF, which activates all G-proteins, stimulated PLC in both HCC and NA-NL livers to a similar extent."
Verma A, Ali D, Pathak AK - "Fluoride induces DNA damage and cytotoxicity in human hepatocellular carcinoma cells" Toxicological & Environmental Chemistry, 99(1):148–159 (2016) doi:10.1080/02772248.2016.1155380
https://www.tandfonline.com/doi/abs/10. ... 16.1155380
Yu Y, Li L, Yu W, Guan Z -"Fluoride Exposure Suppresses Proliferation and Enhances Endoplasmic Reticulum Stress and Apoptosis Pathways in Hepatocytes by Downregulating Sirtuin-1" Biomed Res Int 2022:7380324 (2022) doi: 10.1155/2022/7380324
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420589/
Wang D, Yin K, Zhang Y, Lu H, Hou L, Zhao H, Xing M - "Novel pathways of fluoride-induced hepatotoxicity: P53-dependent ferroptosis induced by the SIRT1/FOXOs pathway and Nrf2/HO-1 pathway" Comp Biochem Physiol C Toxicol Pharmacol 264:109526 (2022). doi: 10.1016/j.cbpc.2022.109526.
https://pubmed.ncbi.nlm.nih.gov/36455829/
National Toxicology Program [NTP] - "Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3f1 Mice. Technical report Series No. 393" NIH Publ. No 91-2848 (1990). National Institute of Environmental Health Sciences, Research Triangle Park, N.C. p. 71-73
https://fluoridealert.org/wp-content/up ... p-1990.pdf
Liu YQ - "Promotive action of sodium fluoride on precancerous lesions of hepatocellular carcinoma induced by diethylnitrosamine (DEN) in rats--stereologic study of enzyme histochemistry" Chinese Journal of Pathology 22(5):299-301 (1993)
https://europepmc.org/article/med/8168199
"The results suggest that sodium fluoride promoted the growth of precancerous lesions of the liver induced by DEN in rats, and this has provided some data to the understanding of the relationship between fluorosis and neoplasms."
PFAS
Benninghoff AD, Orner GA, Buchner CH, Hendricks JD, Duffy AM, Williams DE - "Promotion of hepatocarcinogenesis by perfluoroalkyl acids in rainbow trout" Toxicol Sci 125(1):69-78 (2012) doi: 10.1093/toxsci/kfr267
https://academic.oup.com/toxsci/article ... 69/1668619
"Overall, these data suggest that multiple PFAAs can promote liver cancer and that the mechanism of promotion may be similar to that of E2 [17β-estradiol]."
Bogdanffy MS, Makovec GT, Frame SR - "Inhalation oncogenicity bioassay in rats and mice with vinyl fluoride" Fundam Appl Toxicol 26(2):223-38 (1995) doi: 10.1006/faat.1995.1093
https://pubmed.ncbi.nlm.nih.gov/7589911/
Goodrich JA, Walker D, Lin X, Wang H, Lim T, McConnell R, Conti DV, Chatzi L, Setiawan VW - "Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort" JHEP Rep 4(10):100550 (2022) doi: 10.1016/j.jhepr.2022.100550.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9468464/
"High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 μg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC."
Hong J, Du K, Jin H, Chen Y, Jiang Y, Zhang W, Chen D, Zheng S, Cao L - "Evidence of promoting effects of 6:2 Cl-PFESA on hepatocellular carcinoma proliferation in humans: An ideal alternative for PFOS in terms of environmental health?" Environ Int 186:108582 (2024). doi: 10.1016/j.envint.2024.108582
https://www.sciencedirect.com/science/a ... 2024001685
"Both PFOS and 6:2 Cl-PFES) have been shown to activate the PI3K/AKT/mTOR signaling pathway and inhibit necroptosis. This action consequently enhances the proliferation of HCC cells. Our phenotypic assay findings suggest that the tumorigenic potential of 6:2 Cl-PFESA surpasses that of PFOS; in a subcutaneous tumor model using nude mice, the mean tumor weight for the 6:2 Cl-PFESA-treated cohort was 2.33 times that observed in the PFOS cohort (p < 0.01). Despite 6:2 Cl-PFESA being considered a safer substitute for PFOS, the pronounced effects of this chemical on HCC cell growth warrant a thorough assessment of hepatotoxicity risks linked to its usage."
Lin H, Wu H, Liu F, Yang H, Shen L, Chen J, Zhang X, Zhong Y, Zhang H, Liu Z - "Assessing the hepatotoxicity of PFOA, PFOS, and 6:2 Cl-PFESA in black-spotted frogs (Rana nigromaculata) and elucidating potential association with gut microbiota" Environ Pollut 312:120029 (2022) doi: 10.1016/j.envpol.2022.120029
https://www.sciencedirect.com/science/a ... 912201243X
Alexander BH, Olsen GW, Burris JM, Mandel JH, Mandel JS - "Mortality of employees of a perfluorooctanesulphonyl fluoride manufacturing facility" Occup Environ Med 60(10):722-9 (2003) doi: 10.1136/oem.60.10.722
https://oem.bmj.com/content/60/10/722.short
Yoo HJ, Pyo MC, Park Y, Kim BY, Lee KW - "Hexafluoropropylene oxide dimer acid (GenX) exposure induces apoptosis in HepG2 cells" Heliyon 7(11):e08272 (2021) doi: 10.1016/j.heliyon.2021.e08272
https://www.sciencedirect.com/science/a ... 4021023756
[HepG2 --> hepatocellular carcinoma cell line]
Gq/11 [ERK]
Yu HP, Zheng Y, Lu LX, He YJ, Liang ZJ, Zhang LX, Wang JK, Qin JW, Li B, Li CY, Wang P, Dang Z, Zhang JC, Yu XH - "Preliminary study on the expression of MIF in HCC tissues and its relationship with ERK1/2 signaling pathway" Chinese Journal of Internal Medicine 61(11):1228-1233 (2022). doi: 10.3760/cma.j.cn112138-20220502-00334
https://pubmed.ncbi.nlm.nih.gov/36323564/
GNA14 (Gq/11 family consists of Gna11, Gna14, Gnaq and Gna15)
Xu C, Li YM, Sun B, Zhong FJ, Yang LY - "GNA14's interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway" Carcinogenesis 42(11):1357-1369 (2021) doi: 10.1093/carcin/bgab098
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598382/
Choi E, Park SJ, Lee G, Yoon SK, Lee M, Lee SK - "The GNAQ T96S Mutation Affects Cell Signaling and Enhances the Oncogenic Properties of Hepatocellular Carcinoma" Int J Mol Sci. 22(6):3284 (2021). doi: 10.3390/ijms22063284
https://www.mdpi.com/1422-0067/22/6/3284
THYROID & TSH
The TSH receptor
Overexpression of TSHR was found in a great majority of HCC [hepatocellular carcinoma] tissues and associated with unfavorable prognosis (Shih et al., 2018).
Shih YL, Huang YH, Lin KH, Chu YD, Yeh CT - "Identification of Functional Thyroid Stimulating Hormone Receptor and TSHR Gene Mutations in Hepatocellular Carcinoma" Anticancer Res 38(5):2793-2802 (2018) doi: 10.21873/anticanres.12523
https://ar.iiarjournals.org/content/38/5/2793.long
Tischoff I, Tannapfel A - "Hepatozelluläres Karzinom und Cholangiokarzinom--Unterschiedliche Prognose, Pathogenese und Therapie" [Hepatocellular carcinoma and cholangiocarcinoma--different prognosis, pathogenesis and therapy]. Zentralbl Chir 132(4):300-5(2007)
TPO
Xie RT, Li QY, Sun XC, Zhi QJ, Huang XX, Zhu XC, Miao QZ, Zhou DZ, Han DY - "Hypomethylation of Thyroid Peroxidase as a Biomarker for Hepatocellular Carcinoma with Tumor Thrombosis" Curr Med Sci 42(6):1248-1255 (2022) doi: 10.1007/s11596-022-2643-z.
https://link.springer.com/article/10.10 ... 022-2643-z
"Thyroid hormones (THs) regulate multiple physiological activities in the liver, including cellular metabolism, differentiation, and cell growth, and play important roles in the pathogenesis of hepatocellular carcinoma (HCC)."
DEIODINASES
Essential Reading:
Nappi A, De Stefano MA, Dentice M, Salvatore D - "Deiodinases and Cancer" Endocrinology 162(4):bqab016 (2021) doi: 10.1210/endocr/bqab016
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906444/
D1
Ridruejo E, Romero Caimi G, Miret N, Obregón MJ, Randi A, Deza Z, Kleiman de Pisarev D, Alvarez L - "TGF-β1 mediates cell proliferation and development of hepatocarcinogenesis by downregulating deiodinase 1 expression" Medicina (B Aires) 81(3):346-358 (2021)
https://www.medicinabuenosaires.com/PMID/34137693.pdf
"Results suggest that alteration of TH homeostasis, through D1 function, play a key role in hepatocyte proliferation and that TGF-β1-SMAD pathway is involved in this process confirming their role in early neoplastic transformation in HCC."
Serra M, Pal R, Puliga E, Sulas P, Cabras L, Cusano R, Giordano S, Perra A, Columbano A, Kowalik MA - "mRNA-miRNA networks identify metabolic pathways associated to the anti-tumorigenic effect of thyroid hormone on preneoplastic nodules and hepatocellular carcinoma" Front Oncol 12:941552 (2022). doi: 10.3389/fonc.2022.941552
https://pubmed.ncbi.nlm.nih.gov/36203462/
"Among miRs down-regulated in preneoplastic nodules following T3, co-expression networks revealed those targeting thyroid hormone receptor-β (Thrβ) and deiodinase1, and Oxidative Phosphorylation. On the other hand, miRs targeting members of the Nrf2 Oxidative Pathway, Glycolysis, Pentose Phosphate Pathway and Proline biosynthesis - all involved in the metabolic reprogramming displayed by preneoplastic lesions- were up-regulated."
D2
Nappi A, Miro C, Pezone A, Tramontano A, Di Cicco E, Sagliocchi S, Cicatiello AG, Murolo M, Torabinejad S, Abbotto E, Caiazzo G, Raia M, Stornaiuolo M, Antonini D, Fabbrocini G, Salvatore D, Avvedimento VE, Dentice M - "Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage" Nat Commun 14(1):1244 (2023) doi: 10.1038/s41467-023-36755-y
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9985592/
"Here, we report that p53 physically binds to Dio2 gene, encoding for the D2 protein, promoter, and suppresses D2 expression, both at mRNA and protein levels, thus causing a reduction in intracellular active TH transactivation ability. Strikingly, we observed that D2 expression levels faithfully mirror the p53 status and function in vivo and in vitro....Furthermore, in vivo ablation of D2 reduces the tumorigenesis dependent on the loss of p53, demonstrating a causative link between p53 depletion, the upregulation of D2 and the consequent evolution of cancer toward the invasive phenotype. "
D3
Cui W, Huang Z, He H, Gu N, Qin G, Lv J, Zheng T, Sugimoto K, Wu Q - "MiR-1188 at the imprinted Dlk1-Dio3 domain acts as a tumor suppressor in hepatoma cells" Mol Biol Cell 26(8):1416-27 (2015) doi: 10.1091/mbc.E14-11-1576
https://www.molbiolcell.org/doi/10.1091/mbc.E14-11-1576
"Recent studies indicate that the miRNAs within the Dlk1-Dio3 genomic region are involved in the development of liver cancer..."
Luk JM, Burchard J, Zhang C, Liu AM, Wong KF, Shek FH, Lee NP, Fan ST, Poon RT, Ivanovska I, Philippar U, Cleary MA, Buser CA, Shaw PM, Lee CN, Tenen DG, Dai H, Mao M - "DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival" J Biol Chem 286(35):30706-30713 (2011) doi: 10.1074/jbc.M111.229831
https://www.jbc.org/article/S0021-9258( ... 7/fulltext
Wang Y, Sun P, Hao X, Cao D, Liu J, Zhang D - "Decreased DIO3OS Expression Predicts Poor Prognosis in Hepatocellular Carcinoma and is Associated with Immune Infiltration" Biochem Genet. 2023 Feb 21. doi: 10.1007/s10528-023-10345-5
https://link.springer.com/article/10.10 ... 23-10345-5
[DIO3OS, also known as DIO3 opposite strand/antisense RNA (DIO3OS), is a long non-coding RNA (lncRNA) gene located on human chromosome 14q32. The "OS" in DIO3OS stands for 'opposite strand', indicating that it is transcribed from the opposite DNA strand to the neighboring DIO3 gene.]