Prognostic Value of Promoter Hypermethylation of Retinoic Acid Receptor Beta (RARB) and CDKN2 (p16/MTS1) in Prostate Cancer

Objective: The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients. Methods: In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and 21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of RARB and p16 promoters by methylation specific PCR (MSPCR). Results: Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation, which were significantly higher than controls (P <0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16). Conclusion: Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer.

RARRES2's impact on lipid metabolism in triplenegative breast cancer:a pathway to brain metastasis

Breast cancer brain metastasis(BCBrM)is a crucial and hard area of research which guarantees an urgent need to understand the underlying molecular mechanisms.A recent study by Li et al.[1]published in Military Medical Research investigated the role of retinoic acid receptor responder 2(RARRES2)in regulating lipid metabolism in BCBrM,highlighting the clinical relevance of alterations in lipid metabolites,such as phosphatidylcholine(PC)and triacylglycerols(TAGs),by RARRES2 through the modulation of phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway.This commentary aims to elaborate on the key findings and their relevance to the field.

Retinoic acid receptor responder 2 and lipid metabolic reprogramming:A new insight into brain metastasis

The brain is one of the most common metastatic sites for carcinoma,especially for breast cancer,the second leading cause of brain metastases(BrM)after lung cancer[1].During organ‐tropic metastases,cancer cells have to survive and expand in target organs through a process involving a complex interplay between invading cells and the microenvironment.

Retinoid X receptor α downregulation is required for tail and caudal spinal cord regeneration in the adult newt

Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.

Involvement of chromatin and histone acetylation in the regulation of HIV-LTR by thyroid hormone receptor

The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.

Retinoic acid receptor β is required for anti-activator protein-1 activity by retinoic acid in gastric cancer cells

Objective To investigate the role of retinoic acid receptor β (RARβ) in mediating inhibitory effect of all-trans retinoic acid (ATRA) on activator protein-1 (AP-1) activity in gastric cancer cells. Methods Transient transfection and chloramphenicol acetyltransferase (CAT) assay, Northern blot, gene transfection, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and anchorage-independent growth assay were used.Results Transient transfection of RARβ expression vector into MKN-45 cells resulted in the RARβ concentration-dependent repression of AP-1 activity induced by 12-o-tetradecanoylphorbol-13-acetate (TPA), regardless of the presence of ATRA. When the c-jun and c-fos expression vectors were cotransfected with the RARβ expression vector into MKN-45 cells, AP-1 activity was also obviously repressed. The inhibitory effect, again, was RARβ-concentration-dependent. The stable transfection of the RARβ gene into MKN-45 cells led to cell growth inhibition and colony formation inhibition by ATRA. Furthermore, Cotransfection of both RARβ/DNA binding domain (DBD) and reporter gene could not alter AP-1 activity, even in the presence of ATRA. However, when the cotransfection was substituted with the RARβ/ligand binding domain (LBD), the inhibition was significantly enhanced by ATRA. Conclusion RARβ might be required for anti-AP-1 activity, and contribute to growth inhibition of gastric cancer cells by ATRA.

Decreased expression of type Ⅱ tumor suppressor gene RARRES3 in tissues of hepatocellular carcinoma and cholangiocarcinoma

AIM: To analyze the expression of retinoic acid receptor responder 3 (RARRES3) protein in paraffin-embedded tissues of hepatocellular carcinoma (HCC) and cholangiocarcinoma(CC), and the correlation of RARRES3 production with tumor differentiation.METHODS: Expression of RARRES3 in tissues from 21CC (10 well-, 7 moderately- and 4 poorly-differentiated)and 32 HCC was determined by immunohistochemistry.RESULTS: Among 21 CC tissues, RARRES3 was detected in 8 (80%) of 10 well-differentiated tumors. Only 2 (18.2%)out of 11 tumors with moderate or poor differentiation showed positive RARRES3 expression. RARRES3 expression in well-differentiated CC was significantly higher than that in tumors with moderate or poor differentiation (Fisher exact test, P＜0.01). Expression of RARRES3 was not different between early (Ⅰ and Ⅱ) and late (Ⅲ and Ⅳ) stages of CC.Among 30 HCC tissues, 17 (56.7%) weakly expressed RARRES3 in HCC cells, and 25 (83.3%) normal tissues adjacent to HCC expressed the protein. RARRES3 expression was significantly decreased in HCC tissues compared to that in adjacent normal tissues (logistic regression analysis, OR = 0.27, 95% CI (0.11-0.62), P＜0.01).CONCLUSION: Expression of RARRES3 is positively correlated to well-differentiated CC, which supports the role of RARRES3 in malignant epithelial differentiation of the tumor. The decrease in RARRES3 expression in tissues of HCC and CC with moderate and poor differentiation suggests that altered RARRES3 expression may play a role in the carcinogenesis of the liver and biliary tract.

Mechanism of inhibition on activator protein 1 activity by all trans retinoic acid in gastric cancer cells

To determine the mechanism of all trans retinoic acid (ATRA) on growth inhibition in human gastric cancer cells Methods Gastric cancer cell lines: MGC80 3, BGC 823, SGC 7901 and MKN 45 CAT assay, Northern blot, Western blot, gene transfection and MTT assay Results ATRA can inhibit the activator protein 1 (AP 1) activity in ATRA sensitive cell lines, but not in ATRA resistant cell line, and the anti AP 1 activity of ATRA is mediated by its receptor, retinoic acid receptor α (RARα) ATRA can also inhibit the expression of cJun and cFos One of the mechanisms for ATRA to inhibit the growth of gastric cancer cells may be through its inhibitory effect on the AP 1 activity and its influence on up regulation of RARα expression The inhibition of cJun and cFos expressions by ATRA may also contribute to the anti AP 1 activity Conclusions ATRA inhibits the growth of gastric cancer cells through the regulation of AP 1 activity This action is mediated by RARα

A TDG/CBP/RARα Ternary Complex Mediates the Retinoic Acid-dependent Expression of DNA Methylation-sensitive Genes

The thymine DNA glycosylase （TDG） is a multifunctional enzyme,which is essential for embryonic development.It mediates the base excision repair （BER） of G：T and G：U DNA mismatches arising from the deamination of 5-methyl cytosine （5-MeC） and cytosine,respectively.Recent studies have pointed at a role of TDG during the active demethylation of 5-MeC within CpG islands.TDG interacts with the histone acetylase CREB-binding protein （CBP） to activate CBP-dependent transcription.In addition,TDG also interacts with the retinoic acid receptor α （RARα）,resulting in the activation of RARα target genes.Here we provide evidence for the existence of a functional ternary complex containing TDG,CBP and activated RARα.Using global transcriptome profiling,we uncover a coupling of de novo methylation-sensitive and RA-dependent transcription,which coincides with a significant subset of CBP target genes.The introduction of a point mutation in TDG,which neither affects overall protein structure nor BER activity,leads to a significant loss in ternary complex stability,resulting in the deregulation of RA targets involved in cellular networks associated with DNA replication,recombination and repair.We thus demonstrate for the first time a direct coupling of TDG＇s epigenomic and transcription regulatory function through ternary complexes with CBP and RARα.

The role of tazarotene-induced gene 1 in carcinogenesis:is it a tumor suppressor gene or an oncogene?

Tazarotene-induced gene 1(TIG1)is induced by a derivative of vitamin A and is known to regulate many important biological processes and control the development of cancer.TIG1 is widely expressed in various tissues;yet in many cancer tissues,it is not expressed because of the methylation of its promoter.Additionally,the expression of TIG1 in cancer cells inhibits their growth and invasion,suggesting that TIG1 acts as a tumor suppressor gene.However,in some cancers,poor prognosis is associated with TIG1 expression,indicating its protumor growth characteristics,especially in promoting the invasion of inflammatory breast cancer cells.This review comprehensively summarizes the roles of the TIG1 gene in cancer development and details the mechanisms through which TIG1 regulates cancer development,with the aim of understanding its various roles in cancer development.

Tc17 cells inautoimmune diseases

Multiple sclerosis(MS)and experimental autoimmune encephalomyelitis(EAE),a pathologically similar disease used to model MS in rodents,are typical CD4^(^(+))T cell-dominated autoimmune diseases.CD4^(+)interleukin(IL)17^(+)T cells(Th17 cells)have been well studied and have shown that they play a critical role in the pathogenesis of MS/EAE.However,studies have suggested that CD8^(+)IL17^(+)T cells(Tc17 cells)have a similar phenotype and cytokine and transcription factor profiles to those of Th17 cells and have been found to be crucial in the pathogenesis of autoimmune diseases,including MS/EAE,psoriasis,type I diabetes,rheumatoid arthritis,and systemic lupus erythematosus.However,the evidence for this is indirect and insufficient.Therefore,we searched for related publications and attempted to summarize the current knowledge on the role of Tc17 cells in the pathogenesis of MS/EAE,as well as in the pathogenesis of other autoimmune diseases,and to find out whether Tc17 cells or Th17 cells play a more critical role in autoimmune disease,especially in MS and EAE pathogenesis,or whether the interaction between these two cell types plays a critical role in the development of the disease.