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1.
Fetal Alcohol Spectrum Disorder: Embryogenesis Under Reduced Retinoic Acid Signaling Conditions.
Fainsod, A, Bendelac-Kapon, L, Shabtai, Y
Sub-cellular biochemistry. 2020;:197-225
Abstract
Fetal Alcohol Spectrum Disorder (FASD) is a complex set of developmental malformations, neurobehavioral anomalies and mental disabilities induced by exposing human embryos to alcohol during fetal development. Several experimental models and a series of developmental and biochemical approaches have established a strong link between FASD and reduced retinoic acid (RA) signaling. RA signaling is involved in the regulation of numerous developmental decisions from patterning of the anterior-posterior axis, starting at gastrulation, to the differentiation of specific cell types within developing organs, to adult tissue homeostasis. Being such an important regulatory signal during embryonic development, mutations or environmental perturbations that affect the level, timing or location of the RA signal can induce multiple and severe developmental malformations. The evidence connecting human syndromes to reduced RA signaling is presented here and the resulting phenotypes are compared to FASD. Available data suggest that competition between ethanol clearance and RA biosynthesis is a major etiological component in FASD.
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2.
Inhibition of UBE2L6 attenuates ISGylation and impedes ATRA-induced differentiation of leukemic cells.
Orfali, N, Shan-Krauer, D, O'Donovan, TR, Mongan, NP, Gudas, LJ, Cahill, MR, Tschan, MP, McKenna, SL
Molecular oncology. 2020;(6):1297-1309
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Abstract
Ubiquitin/ISG15-conjugating enzyme E2L6 (UBE2L6) is a critical enzyme in ISGylation, a post-translational protein modification that conjugates the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), to target substrates. Previous gene expression studies in acute promyelocytic leukemia (APL) cells showed that all-trans-retinoic acid (ATRA) altered the expression of many genes, including UBE2L6 (200-fold) and other members of the ISGylation pathway. Through gene expression analyses in a cohort of 98 acute myeloid leukemia (AML) patient samples and in primary neutrophils from healthy donors, we found that UBE2L6 gene expression is reduced in primary AML cells compared with normal mature granulocytes. To assess whether UBE2L6 expression is important for leukemic cell differentiation-two cell line models were employed: the human APL cell line NB4 and its ATRA-resistant NB4R counterpart, as well as the ATRA-sensitive human AML HL60 cells along with their ATRA-resistant subclone-HL60R. ATRA strongly induced UBE2L6 in NB4 APL cells and in ATRA-sensitive HL60 AML cells, but not in the ATRA-resistant NB4R and HL60R cells. Furthermore, short hairpin (sh)RNA-mediated UBE2L6 depletion in NB4 cells impeded ATRA-mediated differentiation, suggesting a functional role for UBE2L6 in leukemic cell differentiation. In addition, ATRA induced ISG15 gene expression in NB4 APL cells, leading to increased levels of both free ISG15 protein and ISG15 conjugates. UBE2L6 depletion attenuated ATRA-induced ISG15 conjugation. Knockdown of ISG15 in NB4 APL cells inhibited ISGylation and also attenuated ATRA-induced differentiation. In summary, we demonstrate the functional importance of UBE2L6 in ATRA-induced neutrophil differentiation of APL cells and propose that this may be mediated by its catalytic role in ISGylation.
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Post-translational modification of retinoic acid receptor alpha and its roles in tumor cell differentiation.
Xu, A, Zhang, N, Cao, J, Zhu, H, Yang, B, He, Q, Shao, X, Ying, M
Biochemical pharmacology. 2020;:113696
Abstract
Retinoic acid (RA) is a well-known differentiation inducer that exerts its effects by binding to nuclear RA receptors. Retinoic acid receptor α (RARα), as an important nuclear RA receptor, is activated upon RA binding and facilitates the transcription of target genes related to differentiation, which ultimately initiates cell differentiation. Previous studies have found that the transcriptional activity of RARα is regulated by various post-translational modifications, which influence its DNA binding efficiency, transactivation ability and even lead to degradation. Post-translational modifications of RARα, as a consequence, play an important role in the RA-induced differentiation process. Therefore, in this review, we focus on recent advances in the understanding of how these modifications affect the activity of RARα as well as strategies to increase the differentiation effect of RA treatment in cancer cells based on RARα modifications, which may promote the development of novel effective differentiation therapies for cancer treatment.
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4.
Upregulation of amphiregulin by retinoic acid and Wnt signalling promotes liver cancer cell proliferation.
Lin, HH, Peng, YJ, Tsai, MJ, Wu, YY, Tsai, TN, Huang, HH, Shih, YL, Chang, WK, Hsieh, TY
Journal of cellular physiology. 2020;(2):1689-1699
Abstract
Activated hepatic stellate cells promote hepatocellular carcinoma (HCC) progression. Hepatic stellate cells play a key role in retinoid metabolism, and activation of stellate cells increases retinoic acid (RA) in the liver. However, the role of RA in HCC proliferation remains unclear. We aimed to analyse the mechanism of RA in HCC proliferation. Thirty-eight patients who had undergone hepatic resection for HCCs were recruited. Paired non-tumour tissues, adjacent and distal to HCCs, were collected, and the RA levels in the tissues were analysed. The mechanisms of RA and HCC proliferation were assessed in liver cancer cell lines by protein and gene expression analyses. Early recurrence of HCC was significantly higher in patients with a higher RA concentration than in those with a lower RA concentration in tissues adjacent to HCCs (61.1% vs. 20%, p = .010). RA promoted HCC cell proliferation and activated the expression of Amphiregulin, a growth factor in hepatocarcinogenesis. The promoter of Amphiregulin contained the binding sites of the RA receptor, RXRα. Wnt signalling also activated the expression of Amphiregulin, and the RA and Wnt pathways acted synergistically to increase the expression of Amphiregulin. Furthermore, RXRα interacted with β-catenin and then translocated to the nucleus to activate Amphiregulin. An increased RA concentration in the tissues adjacent to the tumour was associated with an early recurrence of HCC. RA activated the expression of Amphiregulin, and then promoted HCC proliferation, which might partly contribute to early recurrence of HCC after hepatic resection.
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5.
All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes.
Mosquera, N, Rodriguez-Trillo, A, Blanco, FJ, Mera-Varela, A, Gonzalez, A, Conde, C
The Journal of pharmacology and experimental therapeutics. 2020;(2):185-192
Abstract
Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF+ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors. SIGNIFICANCE STATEMENT All-trans retinoic acid (ATRA) reduced the rheumatoid arthritis (RA) fibroblast-like synoviocyte migration and invasiveness and down-regulated gene expression of cell motility and migration genes. At supraphysiological doses, some of these effects were reverted by tumor necrosis factor. Therefore, ATRA could be an RA drug candidate that would require high doses or combined treatment with anti-inflammatory drugs.
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Prospective randomized controlled trial comparing treatment efficacy and tolerance of picosecond alexandrite laser with a diffractive lens array and triple combination cream in female asian patients with melasma.
Wang, YJ, Lin, ET, Chen, YT, Chiu, PC, Lin, BS, Chiang, HM, Huang, YH, Wang, KY, Lin, HY, Chang, TM, et al
Journal of the European Academy of Dermatology and Venereology : JEADV. 2020;(3):624-632
Abstract
BACKGROUND Recent evidence suggests melasma to be a photoaging disorder. Triple combination creams (TCC: fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05%) remain the gold standard treatment. Picosecond alexandrite laser treatment using a diffractive lens array (DLA) has been identified to be effective for improving photoaging conditions. OBJECTIVE We aimed to compare the efficacy and tolerance of the picosecond alexandrite laser with those of DLA and TCC in female Asian patients with melasma. METHODS Twenty-nine patients were randomly assigned to group A1 (3 laser sessions at 4-week intervals), A2 (5 laser sessions at 4-week intervals) or B (TCC daily for at least 8 weeks and then tapered until the final evaluation). The Melasma Area, Severity Index (MASI) score and VISIA were assessed at baseline, week 12 and week 20. By week 20, the follow-up periods for groups A1 and A2 were 3 months and 1 month, respectively. RESULTS Nine, 11 and 6 participants in groups A1, A2 and B completed the study, respectively. MASI scores were significantly improved in all 3 groups at weeks 12 and 20. In groups A1, A2 and B, the improvement rates at week 20 were 53%, 38% and 50%, respectively. VISIA® analysis additionally revealed a significant improvement in spots, porphyria, pores and brown spots after 3 laser sessions (P < 0.05). Group A2 showed greater improvements than group A1 in terms of spots, wrinkles and pores; however, only red areas were significantly different (P < 0.001). All side-effects in the 3 groups were transient and gradually subsided after 1-3 months. CONCLUSION Picosecond alexandrite laser treatment using DLA showed comparable efficacy with TCC for the treatment of melasma. Improvements in texture, spots, wrinkles and pores were observed in the laser groups. Patients with melasma lesions that exhibit telangiectasia may benefit from additional laser treatment sessions.
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Acute myeloid leukemia during pregnancy: a single institutional experience with 17 patients and literature review.
Li, YW, Xu, YF, Hu, W, Qian, SX, Chen, C
International journal of hematology. 2020;(4):487-495
Abstract
Management of acute myeloid leukemia during pregnancy (P-AML) is a challenging endeavor with limited evidence-based information available. To truly achieve the goal of improving P-AML patients, additional evidence-based research is necessary. We retrospectively reviewed cases of 17 patients diagnosed with P-AML, including seven for acute promyelocytic leukemia (APL) from January 2012 to June 2019. Among the non-APL, 90% patients (9/10) ended pregnancy prior to induction chemotherapy. The median intervals between diagnosis and start of chemotherapy were 5 days (range 1-14 days). Four patients elected to delay chemotherapy by more than one week. Of the seven APL patients, six received all-trans retinoic acid (ATRA) before the diagnostic molecular results. Five patients underwent cesarean sections (CS) and all newborns were alive (four preterm and one full-term deliveries). Overall, approximately 94% of the patients (16/17) are currently alive in remission. To treat P-AML patients in a safer manner, balancing the risk of progressing to advanced disease and proceeding with pregnancy is required. We consider a slight delay (less than 14 days) in the termination of pregnancy may not differ the prognosis to patients with non-APL. For APL, patients will benefit from prompt administration of ATRA for highly suspected cases.
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8.
Cellular retinol binding protein 1 transfection reduces proliferation and AKT-related gene expression in H460 non-small lung cancer cells.
Ferlosio, A, Doldo, E, Agostinelli, S, Costanza, G, Centofanti, F, Sidoni, A, Orlandi, A
Molecular biology reports. 2020;(9):6879-6886
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Abstract
In recent years, new treatments with novel action mechanisms have been explored for advanced non-small cell lung cancer (NSCLC). Retinoids promote cancer cell differentiation and death and their trafficking and action is mediated from specific cytoplasmic and nuclear receptors, respectively. The purpose of this study was to investigate the effect of Cellular retinol binding protein-1 (CRBP-1) transfection in H460 human NSCLC cell line, normally not expressing CRBP-1. H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBP-1 gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans Retinoic Acid (atRA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array and results analysed by one-way analysis of variance (ANOVA) or by t-student test. CRBP-1+ showed reduced proliferation and viability in basal condition and after atRA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBP-1+ H460 cells associated to the down-regulation of pAKT/pERK/pEGFR-related genes. In particular, gene array documented the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, p27, Jun. Restoration of CRBP-1 expression in H460 cells reduced proliferation and viability in both basal condition and after atRA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBP-1-related intracellular pathways contribute to counteract NSCLC progression in order to suggest a potential tool to improve efficacy of retinoid anti lung cancer adjuvant therapy.
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Cellular Retinoic-Acid Binding Protein 2 in Solid Tumor.
Jiao, X, Liu, R, Huang, J, Lu, L, Li, Z, Xu, L, Li, E
Current protein & peptide science. 2020;(5):507-516
Abstract
The retinoic acid (RA) signaling pathway is crucial for many biological processes. The RA transporter, Cellular Retinoic-Acid Binding Protein 2 (CRABP2), is abnormally expressed in various tumor types. CRABP2 presents significant effects on tumorous behaviors and functions, including cell proliferation, apoptosis, invasion, migration, metastasis, and angiogenesis. The tumorigenesis mechanism of CRABP2, as both suppressor and promotor, is complicated, therefore, there remains the need for further investigation. Elucidating the regulating mechanisms in a specific stage of the tumor could facilitate CRABP2 to be a biomarker in cancer diagnosis and prognosis. Besides, clarifying the pathways of CRABP2 in cancer development will contribute to the gene-targeted therapy. In this review, we summarized the expression, distribution, and mechanism of CRABP2 in solid tumors. Illuminating the CRABP2 signaling pathway may benefit understanding the retinoid signaling pathway, providing a useful biomarker for future clinical trials.
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10.
Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial.
Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, et al
Leukemia. 2020;(3):914-918