Tazarotene-induced Gene Research Articles

Empagliflozin Attenuates Renal Tubular Ferroptosis in Preeclampsia via Tazarotene-Induced Gene 1

Empagliflozin Attenuates Renal Tubular Ferroptosis in Preeclampsia via Tazarotene-Induced Gene 1

Tazarotene-induced Gene 1 Induces Melanoma Cell Death by Triggering Endoplasmic Reticulum Stress Response.

This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth. The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between TIG1 expression and its downstream genes was analyzed in a melanoma tissue array. TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between TIG1 expression and the expression of HERPUD1, BIP, and DDIT3. Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth. TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.

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

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

Phospholipase A and acyltransferase 4/retinoic acid receptor responder 3 at the intersection of tumor suppression and pathogen restriction.

Phospholipase A and acyltransferase (PLAAT) 4 is a class II tumor suppressor with phospholipid metabolizing abilities. It was characterized in late 2000s, and has since been referred to as 'tazarotene-induced gene 3' (TIG3) or 'retinoic acid receptor responder 3' (RARRES3) as a key downstream effector of retinoic acid signaling. Two decades of research have revealed the complexity of its function and regulatory roles in suppressing tumorigenesis. However, more recent findings have also identified PLAAT4 as a key anti-microbial effector enzyme acting downstream of interferon regulatory factor 1 (IRF1) and interferons (IFNs), favoring protection from virus and parasite infections. Unveiling the molecular mechanisms underlying its action may thus open new therapeutic avenues for the treatment of both cancer and infectious diseases. Herein, we aim to summarize a brief history of PLAAT4 discovery, its transcriptional regulation, and the potential mechanisms in tumor prevention and anti-pathogen defense, and discuss potential future directions of PLAAT4 research toward the development of therapeutic approaches targeting this enzyme with pleiotropic functions.

Synergistic effect of sorafenib with Platycladus orientalis (L) leaf extract on cervical cancer

The extracts of Platycladus orientalis (L.) Franco leaves have shown promising anti-cancer, anti-oxidant and anti-inflammatory potency with the traditional knowledge of healing HPV associated warts. The purpose of this research is to assess the synergistic activity of sorafenib and Platycladus orientalis (L) leaf extraction on cervical cancer cells. The cytotoxicity efficiency of different concentrations of Sorafenib and ethanol extract of Platycladus orientalis (L.) leaves were tested on HeLa cells by MTT and Trypan blue assays. The synergistic effect of the IC50 concentrations of Sorafenib and Platycladus orientalis (L.) on HeLa cell by MTT assay, and mRNA expression levels of tumor suppressor tazarotene-induced gene 3 (TIG3), proliferating cell nuclear antigen (PCNA) gene and apoptosis modulator (Bcl-2) gene by RT-PCR were evaluated with individual treatments. Combination treatment showed a relatively more expression of TIG3 and less expression of Bcl-2 and PCNA was observed. Growth factor-induced MAPKP activation was arrested by compound combination treatment, which and suppression of proliferation-induced apoptosis of cervical cancer cells. Based on the our results, the combination of sorafenib and crude leaf extract from Platycladus orientalis (L.) can effectively suppress cervical cancer cell growth, thereby providing an interesting rationale for further clinical trials and in-vivo studies.

Tazarotene-induced gene 1 interacts with Polo-like kinase 2 and inhibits cell proliferation in HCT116 colorectal cancer cells.

Tazarotene-induced gene 1 (TIG1) is considered to be a tumor suppressor gene that is highly expressed in normal or well-differentiated colon tissues, while downregulation of TIG1 expression occurs in poorly differentiated colorectal cancer (CRC) tissues. However, it is still unclear how TIG1 regulates the tumorigenesis of CRC. Polo-like kinases (Plks) are believed to play an important role in regulating the cell cycle. The performance of PLK2 in CRC is negatively correlated with the differentiation status of CRC tissues. Here, we found that PLK2 can induce the growth of CRC cells and that TIG1 can prevent PLK2 from promoting the proliferation of CRC cells. We also found that the expression of PLK2 in CRC cells was associated with low levels of Fbxw7 protein and increased expression of cyclin E1. When TIG1 was coexpressed with PLK2, the changes in Fbxw7/cyclin E1 levels induced by PLK2 were reversed. In contrast, silencing TIG1 promoted the proliferation of CRC, and when PLK2 was also silenced, the proliferation of CRC cells induced by TIG1 silencing was significantly inhibited. The above research results suggest that TIG1 can regulate the tumorigenesis of CRC by regulating the activity of PLK2.

Immunohistochemical expression of Tazarotene-induced Gene 3 in oral squamous cell carcinoma.

The prognosis of hyperproliferative skin lesions, such as psoriasis, basal cell carcinoma, and non-melanoma skin cancers, is significantly benefited from the levels of tazarotene-induced gene-1 (TIG3) expression and subsequent treatment with tazarotene. Such observations suggest that TIG3 could be used as a biomarker for apoptosis, differentiation, and proliferation. The current study aimed to evaluate the expression of TIG3 in normal oral mucosa (NOM) and oral squamous cell carcinoma (OSCC) compared with normal skin (NS) and skin squamous cell carcinoma (SSCC) using immunohistochemistry. Seventeen cases each of SSCC, OSCC, NOM, and NS were evaluated. Each section was immunohistochemically stained with a rabbit polyclonal TIG3 antibody. The entire procedure was blinded and evaluated by 5 observers. Statistical analysis was performed using the chi-square test. There was a significant decrease in TIG3 protein expression in OSCC and SSCC compared with that in NOM and NS (P=0.008). The progressive loss of expression was observed as the grade of both malignancies increased. However, there was no significant difference in the expression among the normal tissue groups and within SCC groups of similar grades. The present study suggests that the loss of TIG3 is an important event in carcinogenesis. TIG3 acts as a regulator of keratinocyte proliferation and terminal differentiation. Therefore, TIG3 could be a potential biomarker to differentiate aggressive and non-aggressive neoplasms.

Cathepsin V Mediates the Tazarotene-induced Gene 1-induced Reduction in Invasion in Colorectal Cancer Cells.

Tazarotene-induced gene 1 (TIG1) is a retinoid acid receptor-responsive gene involved in cell differentiation and tumorigenesis. Aberrant methylation of CpG islands in the TIG1 promoter is found in multiple cancers. Currently, the exact mechanism underlying the anticancer effect of TIG1 is unknown. Here, we show that TIG1 interacts with cathepsin V (CTSV), which reduces CTSV stability and subsequently affects the production of activated urokinase-type plasminogen activator (uPA), an epithelial-mesenchymal transition-associated protein. Ectopic expression of CTSV increased the expression of activated uPA and the number of migrated and invaded cells, whereas ectopic TIG1 expression reversed the effects of CTSV on the uPA signaling pathway. Similar patterns in the production of activated uPA and number of migrated and invaded cells were also observed in TIG1-expressing and CTSV-knockdown cells. The results suggest that CTSV may participate in TIG1-regulated uPA activity and the associated downstream signaling pathway.

Chemerin as a Driver of Hypertension: A Consideration.

The protein chemerin (tazarotene-induced gene, TIG2; RARRES2) is a relatively new adipokine. Many studies support that circulating chemerin levels associate strongly and positively with body mass index, visceral fat, and blood pressure. Here, we focus on the specific relationship of chemerin and blood pressure with the goal of understanding whether and how chemerin drives (pathological) changes in blood pressure such that it could be interfered with therapeutically. We dissect the biosynthesis of chemerin and how current antihypertensive medications change chemerin metabolism. This is followed with a review of what is known about where chemerin is synthesized in the body and what chemerin and its receptors can do to the physiological function of organs important to blood pressure determination (e.g., brain, heart, kidneys, blood vessels, adrenal, and sympathetic nervous system). We synthesize from the literature our best understanding of the mechanisms by which chemerin modifies blood pressure, with knowledge that plasma/serum levels of chemerin may be limited in their pathological relevance. This review reveals several gaps in our knowledge of chemerin biology that could be filled by the collective work of protein chemists, biologists, pharmacologists, and clinicians.

Tazarotene-Induced Gene 1 (TIG1) Interacts with Serine Protease Inhibitor Kazal-Type 2 (SPINK2) to Inhibit Cellular Invasion of Testicular Carcinoma Cells.

Tazarotene-induced gene 1 (TIG1) encodes a protein that is a retinoid-regulated tumor suppressor. TIG1 is expressed in most normal tissues, and downregulation of TIG1 expression in multiple cancers is caused by promoter hypermethylation. Kazal-type serine protease inhibitor-2 (SPINK2) is a serine protease inhibitor, and the SPINK protein family has been shown to inhibit the expression of urokinase-type plasminogen activator (uPA). In addition, increased levels of uPA and the uPA receptor were observed in testicular cancer tissues. This study demonstrated that TIG1 interacts with SPINK2 in NT2/D1 testicular carcinoma cells. TIG1 and SPINK2 were highly expressed in normal testis tissues, while low expression levels of TIG1 and SPINK2 were found in testicular cancer tissues. TIG1 inhibited cell invasion, migration, and epithelial–mesenchymal transition (EMT) of NT2/D1 cells. SPINK2 enhanced TIG1-regulated uPA activity and EMT suppression, while silencing SPINK2 alleviated TIG1-mediated EMT regulation, cell migration, and invasion. Therefore, the results suggest that the interaction between TIG1 and SPINK2 plays an important role in the inhibition of testicular cancer cell EMT, and suppression is mediated through downregulation of the uPA/uPAR signaling pathway.

Building a sequence map of the pig pan-genome from multiple de novo assemblies and Hi-C data.

Pigs were domesticated independently in the Near East and China, indicating that a single reference genome from one individual is unable to represent the full spectrum of divergent sequences in pigs worldwide. Therefore, 12 de novo pig assemblies from Eurasia were compared in this study to identify the missing sequences from the reference genome. As a result, 72.5 Mb of non-redundant sequences (∼3% of the genome) were found to be absent from the reference genome (Sscrofa11.1) and were defined as pan-sequences. Of the pan-sequences, 9.0 Mb were dominant in Chinese pigs, in contrast with their low frequency in European pigs. One sequence dominant in Chinese pigs contained the complete genic region of the tazarotene-induced gene 3 (TIG3) gene which is involved in fatty acid metabolism. Using flanking sequences and Hi-C based methods, 27.7% of the sequences could be anchored to the reference genome. The supplementation of these sequences could contribute to the accurate interpretation of the 3D chromatin structure. A web-based pan-genome database was further provided to serve as a primary resource for exploration of genetic diversity and promote pig breeding and biomedical research.

Regulation of Chemerin and CMKLR1 Expression by Nutritional Status, Postnatal Development, and Gender.

Chemerin (also known as tazarotene-induced gene 2 and retinoic acid receptor responder 2) has been identified as an adipokine that exerts effects on many biological processes, including adipogenesis, angiogenesis, inflammation, immune responses, and food intake. This variety of effects has led to its implication in obesity and co-morbidities including diabetes and a risk of cardiovascular disease. The biological effects are mostly mediated by a so-called G protein-coupled receptor, chemokine-like receptor 1 (CMKLR1). Given the association of chemerin with obesity and related diseases, we decided to study in detail the regulation of chemerin and CMKLR1 expression in white adipose tissue (WAT). Specifically, we focused on their expression levels in physiological and pathophysiological settings involved in energy balance: e.g., fasting, postnatal development, and gender. We used Sprague Dawley rats with different nutritional statuses, levels of hormonal deficiency, and states of development as well as ob/ob (leptin-deficient) mice. We analysed the protein expression of both the ligand and receptor (chemerin and CMKLR1) in gonadal WAT by western blotting. We found that chemerin and CMKLR1 protein levels were regulated in WAT by different conditions associated with metabolic changes such as nutritional status, sex steroids, pregnancy, and food composition. Our data indicate that regulation of the expression of this new adipokine and its receptor by nutritional status and gonadal hormones may be a part of the adaptive mechanisms related to altered fat mass and its metabolic complications.

Tazarotene-Induced Gene 1 Interacts with DNAJC8 and Regulates Glycolysis in Cervical Cancer Cells.

The tazarotene-induced gene 1 (TIG1) protein is a retinoid-inducible growth regulator and is considered a tumor suppressor. Here, we show that DnaJ heat shock protein family member C8 (DNAJC8) is a TIG1 target that regulates glycolysis. Ectopic DNAJC8 expression induced the translocation of pyruvate kinase M2 (PKM2) into the nucleus, subsequently inducing glucose transporter 1 (GLUT1) expression to promote glucose uptake. Silencing either DNAJC8 or PKM2 alleviated the upregulation of GLUT1 expression and glucose uptake induced by ectopic DNAJC8 expression. TIG1 interacted with DNAJC8 in the cytosol, and this interaction completely blocked DNAJC8-mediated PKM2 translocation and inhibited glucose uptake. Furthermore, increased glycose uptake was observed in cells in which TIG1 was silenced. In conclusion, TIG1 acts as a pivotal repressor of DNAJC8 to enhance glucose uptake by partially regulating PKM2 translocation.

Arabidopsis Homologues to the LRAT a Possible Substrate for New Plant-Based Anti-Cancer Drug Development

This article describes how an NC gene family has been identified in the genome of the Arabidopsis thaliana (Arabidopsis) by homology to the human Lecithin Retinal Acyl Transferase (LRAT) and the picornavirus 2A protein. The Arabidopsis proteins contain two motifs identified in a vast variety of organisms, an H-Box and an NC. Among related proteins are the C. elegans EGL-26, a regulator protein of cell morphogenesis in the vulva region, and human proteins that might be related to cell proliferation or development. Human homologues include HRAS-like tumour suppressors, the Tazarotene-induced gene 3 (TIG3), and a deSumoylating Isopeptidase (PNAS-4) that induces apoptosis in lung cancer cells. Preservation of the two motifs observed in the Arabidopsis proteins in homology to tumour suppressors, and the conservation of residues important for the function of the LRAT amongst the Arabidopsis homologues can be indicative not only of the importance of these domains for the function of the plant proteins but can also reveal a new candidate group for the design of plant-based tumour-targeting drug development.

Multiple roles of RARRES1 in prostate cancer: Autophagy induction and angiogenesis inhibition.

BackgroundProstate cancer (PCa) poses a major health concern in men worldwide. Retinoic Acid Receptor Responder (RARRES1)/ Tazarotene-induced gene-1 (TIG-1) is a putative tumor suppressor gene that exerts its tumor suppressor function via unknown mechanisms. Epigenetic silencing of RARRES1 leads to its loss in several types of cancer, including PCa. Determining the molecular mechanisms that mediate the tumor suppressor role of RARRES1 in PCa is the focus of our study.FindingsOur data indicates that RARRES1 over expression in PCa cell lines represses mitogen-activated protein kinase (MAPK) activation. RARRES1 expression induces the levels of autophagy-related genes, beclin, ATG3 and increases LC3B-II conversion. A significant induction of SIRT1 along with mTOR inhibition is noted on RARRES1 expression. Furthermore, RARRES1 over expression elevates the levels of the antioxidant enzyme, catalase. Our results also indicate that RARRES1 expression inhibits angiogenesis in endothelial cells.ConclusionsIn summary, the data presented here indicate that forced expression of RARRES1 in PCa cells (a) induces ER stress and autophagic response; (b) increases SIRT1 levels; and (c) higher levels of anti-oxidant enzymes. Our study also implicates the role of RARRES1 as a novel anti-angiogenic molecule. Overall this study reports the molecular players that RARRES1 modulates to serve as a tumor suppressor molecule. Future studies will help determine the in vivo mechanisms by which RARRES1 may serve as a target for therapeutic intervention both in cancer and in angiogenesis-related disorders.

High expression of TIG3 predicts poor survival in patients with primary glioblastoma.

TIG3 (tazarotene-induced gene 3) has been reported to suppress the progression of several malignancies, where this gene is universally downregulated. However, the expression of TIG3 in primary glioblastoma and its relevance to patient's prognosis have not been elaborated. Thus, this study was aimed to evaluate TIG3 expression level in primary glioblastoma and investigate the prognostic value of TIG3 for patients. The Cancer Genome Atlas database was first utilized to analyze the expression and prognostic potential of TIG3 in 528 glioblastoma cases. Compared with control group, glioblastoma showed significantly elevated TIG3 expression (p < 0.001). Log-rank analysis revealed that higher expression of TIG3 was associated with shorter overall survival (358vs 383 days, p = 0.039). Furthermore, TIG3 protein expression detected by immunohistochemistry confirmed positive correlation of TIG3 expression and glioma grade and upregulation of TIG3 in our cohort of 101 primary glioblastoma patients compared to 16 normal brains. Finally, Kaplan-Meier analysis and Cox regression analysis identified high TIG3 expression as an independent risk factor for overall survival of primary glioblastoma patients (overall survival, 10 vs 13 months, p = 0.033; hazard ratio = 1.542, p = 0.046). Together, this study indicated that increased expression of TIG3 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients. We then hypothesize that TIG3 may function in a different pattern in glioblastoma.

Tazarotene-Induced Gene 1 Enhanced Cervical Cell Autophagy through Transmembrane Protein 192.

Tazarotene-induced gene 1 (TIG1) is a retinoic acid-inducible protein that is considered a putative tumor suppressor. The expression of TIG1 is decreased in malignant prostate carcinoma or poorly differentiated colorectal adenocarcinoma, but TIG1 is present in benign or well-differentiated tumors. Ectopic TIG1 expression led to suppression of growth in cancer cells. However, the function of TIG1 in cell differentiation is still unknown. Using a yeast two-hybrid system, we found that transmembrane protein 192 (TMEM192) interacted with TIG1. We also found that both TIG1A and TIG1B isoforms interacted and co-localized with TMEM192 in HtTA cervical cancer cells. The expression of TIG1 induced the expression of autophagy-related proteins, including Beclin-1 and LC-3B. The silencing of TMEM192 reduced the TIG1-mediated upregulation of autophagic activity. Furthermore, silencing of either TIG1 or TMEM192 led to alleviation of the upregulation of autophagy induced by all-trans retinoic acid. Our results demonstrate that the expression of TIG1 leads to cell autophagy through TMEM192. Our study also suggests that TIG1 and TMEM192 play an important role in the all-trans retinoic acid-mediated upregulation of autophagic activity.

Tazarotene-induced gene 2 is associated with poor survival in non-small cell lung cancer.

The aim of the present study was to investigate the expression of tazarotene-induced gene 2 (TIG2) and evaluate the clinicopathological variables and prognostic value for non-small cell lung cancer (NSCLC) patients. Reverse transcription-polymerase chain reaction and western blotting were utilized to detect TIG2 expression in NSCLC specimens and adjacent noncancerous tissue. Furthermore, the present study investigated the protein expression and the clinicopathological significance of TIG2 in 98 paraffin-embedded NSCLC samples by using immunohistochemistry. The results of the present study demonstrated that the expression of TIG2 mRNA (P=0.003) and protein (P=0.0024) was significantly reduced in NSCLC compared with corresponding noncancerous tissue. TIG2 protein expression in NSCLC was significantly associated with lymph node metastasis (P=0.006), Tumor-Node-Metastasis stage (P=0.021) and degree of differentiation (P=0.025). The Kaplan-Meier method and log-rank test revealed that high TIG2 expression was significantly associated with increased survival of NSCLC patients (P=0.003). Multivariate analysis revealed that TIG2 expression was an independent prognostic factor of the overall survival of NSCLC patients. Decreased expression of TIG2 may be useful as a biomarker for poor prognosis in NSCLC carcinogenesis and may act as a target for gene therapy for the treatment of NSCLC patients.

Effect of a tretinoin derivative ECPIRM on retinoic acid receptors and skin irritation responses to it in mice

Objective To estimate the effect of a tretinoin derivative ECPIRM on retinoic acid receptors(RARs), and to observe skin irritation responses to it in mice. Methods Cultured SCL-1 cells were divided into 2 groups to be treated with culture medium containing 10 μmol/L ECPIRM(ECPIRM group)or 10 μmol/L all-trans retinoic acid(ATRA)(ATRA group)for 24 hours, and those treated with drug-free culture medium served as the control group. Western blot analysis and real-time fluorescence-based quantitative PCR were performed to quantify the protein and mRNA expressions of RARs(RARα, RARβ, RARγ and RXRα)respectively. In addition, real-time fluorescence-based quantitative PCR was conducted to measure the mRNA expressions of two target genes of the activated RAR signaling pathway, i.e., cytochrome P450 26A1(CYP26A1)and tazarotene-induced gene 1(TIG1). Eight BALB/c mice were equally divided into 2 groups to be topically treated with 0.075% ECPIRM gel or 0.05% ATRA cream at equal molar concentrations on the shaved skin once daily for 21 successive days. Skin irritation reactions were assessed in these mice. Results Compared with the control group, the ATRA group showed significantly increased protein and mRNA expressions of RARα, RARβ and RARγ(all P 0.05). Obvious Skin irritation reactions such as erythema and desquamation were observed in BALB/c mice after 2-day topical treatment with ATRA cream, and their degree peaked after 5-day treatment. However, neither erythema nor desquamation was observed in BALB/c mice during 21-day treatment with 0.075% ECPIRM gel. Conclusion Unlike ATRA, ECPIRM cannot activate the canonical RAR signaling pathway or cause skin irritation reactions. Key words: Tretinoin; Skin irritancy tests; Mice; ECPIRM; Retinoic acid receptor

The antitumor effect of TIG3 in liver cancer cells is involved in ERK1/2 inhibition.

Tazarotene-induced gene 3 (TIG3) was first characterized in tazarotene-treated human keratinocytes and identified as a retinoic acid responder gene, an important mediator of antitumor effects by retinoids. In this study, we aim to investigate the inhibitory effect of TIG3 on the growth of liver cancer and explore its underlying mechanism. Human hepatocellular carcinoma (HCC) Hep3B cells were transfected with plasmid GV141 carrying full-length TIG3 complementary DNA (cDNA). The effects of TIG3 on cell proliferation, apoptosis, and migration were determined in vitro. The suppressor effect of TIG3 on tumor growth was evaluated in vivo in a nude mouse HCC model. We observed that TIG3 expression is decreased in the Hep3B cell line as well as primary HCC tumors, and TIG3 expression inversely correlates with Ki-67 expression. Overexpression of TIG3 suppresses tumor growth in HCC both in vitro and in vivo via ERK1/2 inhibition by promoting apoptosis and inhibiting proliferation and migration. These findings identify TIG3 as an attractive therapeutic target for HCC.