Gene Summary

Gene:ARNTL; aryl hydrocarbon receptor nuclear translocator like
Aliases: TIC, JAP3, MOP3, BMAL1, PASD3, BMAL1c, bHLHe5
Summary:The protein encoded by this gene is a basic helix-loop-helix protein that forms a heterodimer with CLOCK. This heterodimer binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Defects in this gene have been linked to infertility, problems with gluconeogenesis and lipogenesis, and altered sleep patterns. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:aryl hydrocarbon receptor nuclear translocator-like protein 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (19)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transcription Factors
  • Circadian Clocks
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • eIF-2 Kinase
  • RNA Interference
  • CLOCK Proteins
  • HEK293 Cells
  • siRNA
  • Adenocarcinoma
  • Chromosome 11
  • Promoter Regions
  • Gene Expression Regulation
  • Young Adult
  • ARNTL Transcription Factors
  • DNA Methylation
  • Antineoplastic Agents
  • Gene Expression Profiling
  • Single Nucleotide Polymorphism
  • Stomach Cancer
  • Prostate Cancer
  • Breast Cancer
  • Case-Control Studies
  • Biological Models
  • Period Circadian Proteins
  • Proto-Oncogene Proteins c-myc
  • Nuclear Proteins
  • Neoplasm Invasiveness
  • Mice, Inbred BALB C
  • Colorectal Cancer
  • Basic Helix-Loop-Helix Transcription Factors
  • Western Blotting
  • Circadian Rhythm
  • Cell Proliferation
  • Circadian Rhythm Signaling Peptides and Proteins
  • Melanoma
  • Transfection
  • Signal Transduction
  • Cryptochromes
  • Apoptosis
  • Messenger RNA
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ARNTL (cancer-related)

Yuan C, Jin F, Guo X, et al.
Correlation Analysis of Breast Cancer DWI Combined with DCE-MRI Imaging Features with Molecular Subtypes and Prognostic Factors.
J Med Syst. 2019; 43(4):83 [PubMed] Related Publications
This study aimed to deeply analyze the application of DWI and DCE-MRI imaging in breast cancer, the correlation between the imaging characteristics of DWI and DCE-MRI and the molecular subtypes and prognostic factors of breast cancer was studied. Firstly, DWI and DCE-MRI scans of all patients before interventional therapy were performed, and relevant information of the subjects was introduced in turn. Secondly, molecular subtypes were determined according to immunohistochemical results and gene amplification. Siemens 3.0 T post-processing workstation was used for image post-processing. The time signal curve (TIC), early enhancement rate (EER) and ADC values were measured, morphological characteristics were recorded, and the correlation between each image feature and molecular subtypes, prognostic factors (tumor size, pathological grade, lymph node metastasis, ER, PR, HER2, Ki67) was analyzed. The results showed that parameters such as ADC value, EER, lobulation sign, burr sign, enhancement way and TIC type were correlated with prognostic factors and molecular subtypes. And Bayesian model discriminant analysis showed that the above imaging parameters couldn't well predict the expression of immunohistochemical factors and molecular subtypes. However, the above characteristics had a good effect on the prediction of pathological grade, with a false diagnosis rate of 9.69%.

Orhan T, Nielsen PB, Hviid TVF, et al.
Expression of Circadian Clock Genes in Human Colorectal Cancer Tissues Using Droplet Digital PCR.
Cancer Invest. 2019; 37(2):90-98 [PubMed] Related Publications
Increasing evidence indicates that disruption of circadian rhythms may be directly linked to cancer. Here we report that the expression levels of the core clock genes Per1 and Per3 measured by droplet digital polymerase chain reaction are significantly decreased in tumour tissue from 16 patients undergoing colorectal cancer surgery compared to paired normal mucosa. No differences were observed in the expression of Per2, Bmal1, and Clock. In conclusion, abnormal expression levels of the clock genes Per1 and Per3 in CRC tissue may be related to tumourigenesis and may provide future diagnostic and prognostic information.

Peng H, Zhang J, Zhang PP, et al.
ARNTL hypermethylation promotes tumorigenesis and inhibits cisplatin sensitivity by activating CDK5 transcription in nasopharyngeal carcinoma.
J Exp Clin Cancer Res. 2019; 38(1):11 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Increasing evidence support an important role for DNA methylation in nasopharyngeal carcinoma (NPC). Here, we explored the role of circadian clock gene Aryl Hydrocarbon Receptor Nuclear Translocator-Like (ARNTL) methylation in NPC.
METHODS: We employed bisulfite pyrosequencing to determine the epigenetic change of ARNTL in NPC cell lines and tissues. ARNTL mRNA and protein expression in cell lines and tissues were detected by real-time PCR and western blotting. Then, we constructed cell lines overexpressing ARNTL and knocked down ARNTL to explore its function and effect on chemotherapy sensitivity of NPC cell lines to cisplatin in vitro and vivo. Finally, we investigated the potential molecular mechanism of ARNTL by gene set enrichment analysis (GSEA), dual Luciferase reporter assay and chromatin immunoprecipitation assay.
RESULTS: ARNTL was hypermethylated, and its mRNA and protein were significantly down-regulated in NPC cell lines and tissues. When treated by 5-aza-2'-deoxycytidine, mRNA expression was up-regulated. Overexpression of ARNTL could suppress NPC cells proliferation in vitro and vivo while silencing of ARNTL using shRNA achieved opposite results. GSEA assay found that ARNTL was associated with cell cycle and ectopic ARNTL overexpression could induce G2-M phase arrest. Then, we identified and validated cyclin-dependent kinase 5 (CDK5) as the targeting gene of ARNTL by dual Luciferase reporter assay and chromatin immunoprecipitation assay. When transiently infected ARNTL-overexpression cells with PENTER-vector or PENTER-CDK5 plasmids, the later could reverse the suppressive effects of ARNTL on NPC cell proliferation. Moreover, ARNTL significantly enhanced sensitivity to cisplatin in NPC cells.
CONCLUSIONS: ARNTL suppresses NPC cell proliferation and enhances sensitivity to cisplatin by targeting CDK5. ARNTL may represent a novel therapeutic target for NPC.

Shao M, Yang Q, Zhu W, et al.
LncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation.
Mol Cancer. 2018; 17(1):173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Liver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown.
METHODS: An unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA.
RESULTS: Here, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal.
CONCLUSION: HOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.

Jia Y, Gu D, Wan J, et al.
The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer.
Oncogene. 2019; 38(10):1764-1777 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.

Broadberry E, McConnell J, Williams J, et al.
Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours.
Breast Cancer Res. 2018; 20(1):125 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Circadian rhythms maintain tissue homeostasis during the 24-h day-night cycle. Cell-autonomous circadian clocks play fundamental roles in cell division, DNA damage responses and metabolism. Circadian disruptions have been proposed as a contributing factor for cancer initiation and progression, although definitive evidence for altered molecular circadian clocks in cancer is still lacking. In this study, we looked at circadian clocks in breast cancer.
METHODS: We isolated primary tumours and normal tissues from the same individuals who had developed breast cancer with no metastases. We assessed circadian clocks within primary cells of the patients by lentiviral expression of circadian reporters, and the levels of clock genes in tissues by qPCR. We histologically examined collagen organisation within the normal and tumour tissue areas, and probed the stiffness of the stroma adjacent to normal and tumour epithelium using atomic force microscopy.
RESULTS: Epithelial ducts were disorganised within the tumour areas. Circadian clocks were altered in cultured tumour cells. Tumour regions were surrounded by stroma with an altered collagen organisation and increased stiffness. Levels of Bmal1 messenger RNA (mRNA) were significantly altered in the tumours in comparison to normal epithelia.
CONCLUSION: Circadian rhythms are suppressed in breast tumour epithelia in comparison to the normal epithelia in paired patient samples. This correlates with increased tissue stiffness around the tumour region. We suggest possible involvement of altered circadian clocks in the development and progression of breast cancer.

Song J, Xie C, Jiang L, et al.
Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma.
Theranostics. 2018; 8(13):3571-3583 [PubMed] Free Access to Full Article Related Publications
It has been reported that the transcription factor activating enhancer-binding protein 4 (TFAP4) is upregulated and associated with an aggressive phenotype in several cancers. However, the precise mechanisms underlying the oncogenic role of TFAP4 remain largely unknown.

Fuhr L, El-Athman R, Scrima R, et al.
The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer.
EBioMedicine. 2018; 33:105-121 [PubMed] Free Access to Full Article Related Publications
An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock-regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy.

Lesicka M, Jabłońska E, Wieczorek E, et al.
Altered circadian genes expression in breast cancer tissue according to the clinical characteristics.
PLoS One. 2018; 13(6):e0199622 [PubMed] Free Access to Full Article Related Publications
Breast cancer has a multifactorial etiology. One of the supposed and novel mechanisms is an alteration of circadian gene expression. Circadian genes play a crucial role in many physiological processes. These processes, such as genomic stability, DNA repair mechanism and apoptosis, are frequently disrupted in breast tumors. To assess the significance of circadian gene expression in breast cancer, we carried out an analysis of CLOCK, BMAL1, NPAS2, PER1, PER2, PER3 and CRY1, CRY2, TIMELESS, CSNK1E expression by the use of the quantitative Real-Time PCR technique in tumor tissue and non-tumor adjacent normal tissue sampled from 107 women with a newly diagnosed disease. The obtained data were compared to the clinical and histopathological features. PER1, PER2, PER3, CRY2 were found to be significantly down-expressed, while CLOCK, TIMELESS were over-expressed in the studied tumor samples compared to the non-tumor samples. Only gene expression of CRY1 was significantly down-regulated with progression according to the TNM classification. We found significantly decreased expression of CRY2, PER1, PER2 genes in the ER/PR negative breast tumors compared to the ER/PR positive tumors. Additionally, expression of CRY2, NPAS2 genes had a decreased level in the poorly differentiated tumors in comparison with the well and moderately differentiated ones. Our results indicate that circadian gene expression is altered in breast cancer tissue, which confirms previous observations from various animal and in vitro studies.

Huang G, Jiang H, Lin Y, et al.
LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner.
J Exp Clin Cancer Res. 2018; 37(1):121 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: With self-renewal and differentiation properties, liver tumor initiating cells (TICs) are the reasons for tumor initiation, metastasis and drug resistance. G protein coupled receptors (GPCR) are critical modulators in many physiological and pathological processes. While, their roles in liver TICs are unknown.
METHODS: An unbiased screening was performed using online-available data dataset. Liver TICs were sorted by FACS with surface marker CD133, or enriched by oncosphere formation. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH were used explore the molecular mechanism of lncRNA.
RESULTS: We performed an unbiased screening for GPCR expression in liver cancers, and found GPR107 was the most highly expressed GPCR in liver cancer and liver TICs. GPR107 was essential for the self-renewal of liver TICs. The expression of GPR107 was regulated by a long noncoding RNA lncGPR107. LncGPR107 was also highly expressed in liver cancers and liver TICs. LncGPR107 drove the self-renewal of liver TICs through GPR107. Moreover, lncGPR107 recruited SRCAP complex to GPR107 promoter to drive its transcriptional activation. LncGPR107 depletion inhibited the binding of SRCAP complex and GPR107 promoter and subsequent GPR107 expression. Moreover, LncGPR107-SRCAP-GPR107 can be targeted for liver TIC elimination.
CONCLUSION: GPR107 was the most highly expressed GPCR in liver cancer and liver TICs. LncGPR107 participated in the transcriptional regulation of GPR107 in cis, through recruiting SRCAP remodeling complex to GPR107 promoter. This work revealed the important role of GPCR signaling in liver TIC self-renewal and added a new layer for liver TIC and GPCR regulation.

Wagner PM, Sosa Alderete LG, Gorné LD, et al.
Proliferative Glioblastoma Cancer Cells Exhibit Persisting Temporal Control of Metabolism and Display Differential Temporal Drug Susceptibility in Chemotherapy.
Mol Neurobiol. 2019; 56(2):1276-1292 [PubMed] Related Publications
Even in immortalized cell lines, circadian clocks regulate physiological processes in a time-dependent manner, driving transcriptional and metabolic rhythms, the latter being able to persist without transcription. Circadian rhythm disruptions in modern life (shiftwork, jetlag, etc.) may lead to higher cancer risk. Here, we investigated whether the human glioblastoma T98G cells maintained quiescent or under proliferation keep a functional clock and whether cells display differential time responses to bortezomib chemotherapy. In arrested cultures, mRNAs for clock (Per1, Rev-erbα) and glycerophospholipid (GPL)-synthesizing enzyme genes,

Yu Y, Li Y, Zhou L, et al.
Cryptochrome 2 (CRY2) Suppresses Proliferation and Migration and Regulates Clock Gene Network in Osteosarcoma Cells.
Med Sci Monit. 2018; 24:3856-3862 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Circadian disruption is a potential cancer risk factor in humans. However, the role of the clock gene, cryptochrome 2 (CRY2), in osteosarcoma (OS) is still not clear. MATERIAL AND METHODS To evaluate the potential role of CRY2 in HOS osteosarcoma cells, CRY2-silenced cell lines were established. Furthermore, we investigated the effect of CRY2 knockdown on HOS cells by CCK-8, colony formation, migration assay, and flow cytometry, in vitro. RESULTS CRY2 knockdown promoted HOS OS cell proliferation and migration. We used a cell cycle assay to show that CRY2 knockdown increased the S phase cell population and reduced the G1 phase cell population. Western blot analyses showed that CRY2 knockdown decreased P53 expression and increased expression of c-myc and cyclin D1. Simultaneously, CRY2 knockdown increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, but did not change the phosphorylation of c-Jun N terminal kinase (JNK) and P38. CRY2 knockdown also increased the expression of matrix metalloproteinase (MMP)-2 and β-catenin, and increased OS cell proliferation and migration by inducing cell cycle progression and promoting mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways. Although it has previously been unclear whether the expression of CRY2 affects the expression of other clock genes in the clock gene network, our results show that knockdown of CRY2 significantly increased the mRNA expression of CRY1, Period (PER) 1, PER2, BMAL1, and CLOCK. CONCLUSIONS Our results suggest that CRY2 may be an anti-oncogene in OS, whose functions involve both downstream genes and other circadian genes.

Chen Z, Yao L, Liu Y, Zhu P
LncTIC1 interacts with β-catenin to drive liver TIC self-renewal and liver tumorigenesis.
Cancer Lett. 2018; 430:88-96 [PubMed] Related Publications
Liver tumor-initiating cells (TICs) are drivers of liver tumorigenesis, and Wnt/β-catenin activation plays a principal role in the self-renewal of liver TICs. Despite a deep understanding of Wnt/β-catenin regulation, the roles of long noncoding RNAs (lncRNAs) in Wnt/β-catenin activation and liver TIC self-renewal are largely unknown. Here, we performed unbiased screening of lncRNAs in liver tumorigenesis and found lncTIC1 was highly expressed with liver tumorigenesis. LncTIC1 was also highly expressed in liver TICs and required for the self-renewal of liver TICs. LncTIC1 drove liver TIC self-renewal through Wnt/β-catenin signaling. LncTIC1 interacted with the N terminal of β-catenin and inhibited the phosphorylation of β-catenin, finally maintaining the stability of β-catenin to drive the activation of Wnt/β-catenin signaling. Through β-catenin maintenance and Wnt/β-catenin regulation, lncTIC1 participated in liver TIC self-renewal, liver tumorigenesis and tumor propagation. Moreover, blockade of lncTIC1 signaling greatly inhibited the propagation of liver cancer and liver TICs.

Sánchez DI, González-Fernández B, Crespo I, et al.
Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine-induced hepatocellular carcinoma.
J Pineal Res. 2018; 65(3):e12506 [PubMed] Related Publications
Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg

Huang G, Jiang H, He Y, et al.
LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.
J Exp Clin Cancer Res. 2018; 37(1):105 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored.
METHODS: Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH.
RESULTS: Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression.
CONCLUSION: MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.

Ullmann P, Rodriguez F, Schmitz M, et al.
The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis.
Cancer Res. 2018; 78(14):3793-3808 [PubMed] Related Publications
The vast majority of colorectal cancer-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 (

Morgan H, Olivero C, Patel GK
Identification of Human Cutaneous Basal Cell Carcinoma Cancer Stem Cells.
Methods Mol Biol. 2019; 1879:435-450 [PubMed] Related Publications
The cancer stem cell model states that a subset of tumor cells, called "cancer stem cells," can initiate and propagate tumor growth through self-renewal, high proliferative capacity, and their ability to recreate tumor heterogeneity. In basal cell carcinoma (BCC), we have shown that tumor cells that express the cell surface protein CD200 fulfill the cancer stem cell hypothesis. CD200+ CD45- BCC cells represent 0.05-3.96% of all BCC cells and reside in small clusters at the tumor periphery. Using a novel, reproducible in vivo xenograft growth assay, we determined that tumor-initiating cell (TIC) frequencies are approximately 1 per 1.5 million unsorted BCC cells. The CD200+ CD45- BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200+ CD45- cells, representing ~1500-fold enrichment. The methods used to identify and purify CD200+ CD45- BCC cells, as well as characterize gene expression, are described herein.

Guarnieri AL, Towers CG, Drasin DJ, et al.
The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L.
Oncogene. 2018; 37(28):3879-3893 [PubMed] Free Access to Full Article Related Publications
Tumor-initiating cells (TIC) represent a subset of tumor cells with increased self-renewal capability. TICs display resistance to frontline cancer treatment and retain the ability to repopulate a tumor after therapy, leading to cancer relapse. NOTCH signaling has been identified as an important driver of the TIC population, yet mechanisms governing regulation of this pathway in cancer remain to be fully elucidated. Here we identify a novel mechanism of NOTCH regulation and TIC induction in breast cancer via the miR-106b-25 miRNA cluster. We show that the miR-106b-25 cluster upregulates NOTCH1 in multiple breast cancer cell lines, representing both estrogen receptor (ER+) and triple negative breast cancer (TNBC) through direct repression of the E3 ubiquitin ligase, NEDD4L. We further show that upregulation of NOTCH1 is necessary for TIC induction downstream of miR-106b-25 in both ER + and TNBC breast cancer cells, and that re-expression of NEDD4L is sufficient to reverse miR106b-25-mediated NOTCH1 upregulation and TIC induction. Importantly, we demonstrate a significant positive correlation between miR-106b-25 and NOTCH1 protein, yet a significant inverse correlation between miR-106b-25 and NEDD4L mRNA in human breast cancer, suggesting a critical role for the miR106b-25/NEDD4L/NOTCH1 axis in the disease. Further, we show for the first time that NEDD4L expression alone is significantly associated with a better relapse-free prognosis for breast cancer patients. These data expand our knowledge of the mechanisms underlying NOTCH activation and TIC induction in breast cancer, and may provide new avenues for the development of therapies targeting this resistant subset of tumor cells.

Zhang Y, Duan C, Yang J, et al.
Deubiquitinating enzyme USP9X regulates cellular clock function by modulating the ubiquitination and degradation of a core circadian protein BMAL1.
Biochem J. 2018; 475(8):1507-1522 [PubMed] Related Publications
Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes and their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1). Through biochemical experiments, we discover that USP9X reduces BMAL1 ubiquitination, enhances its stability, and increases its protein level, leading to the elevated transcriptional activity. Bioluminescence measurement reveals that USP9X knockdown decreases the amplitude of the cellular circadian rhythm but the period and phase are not affected. Our experiments find a new regulator for circadian clock at the post-translational level and demonstrate a different regulatory function for the circadian clock through the deubiquitination and the up-regulation of the core clock protein BMAL1 in the positive limb of the transcription-translation feedback loop.

Chen Z, Liu Y, Yao L, et al.
The long noncoding RNA lncZic2 drives the self-renewal of liver tumor-initiating cells via the protein kinase C substrates MARCKS and MARCKSL1.
J Biol Chem. 2018; 293(21):7982-7992 [PubMed] Free Access to Full Article Related Publications
Liver tumor-initiating cells (TICs) form small subsets of cells in hepatocellular tumors and account for tumorigenesis, metastasis, recurrence, and drug resistance. Recently, we found that the transcription factor Zic family member 2 (ZIC2) is highly expressed in liver TICs and required for their self-renewal. However, the molecular mechanisms underlying self-renewal of liver TICs remain unclear. Here, using expression profiling and CRISPR-interference assays with clinical samples of human liver cancers, we identified a long noncoding RNA (lncRNA), lncZic2, that is located near the ZIC2 locus and was highly expressed in liver cancer and liver TICs. We found that lncZic2 is required for the self-renewal of liver TICs in a ZIC2-independent manner. lncZic2 drove the expression of myristoylated alanine-rich protein kinase C substrate (MARCKS) and MARCKS-like 1 (MARCKSL1), whose expression levels were increased during liver tumorigenesis and liver TIC self-renewal. Mechanistically, lncZic2 interacted with BRM/SWI2-related gene 1 (BRG1) and recruited this transcriptional regulator to the promoters of the MARCKS and MARCKSL1 gene, which activated expression of these genes. Moreover, we noted that depletion of lncZic2 and BRG1 decreases MARCKS and MARCKSL1 expression and diminishes liver TIC levels. In conclusion, lncZic2 is required for the self-renewal of liver TICs by up-regulating MARCKS and MARCKSL1 gene expression via the transcription factor BRG1. Our findings suggest that the lncZic2-BRG1-MARCKS/MARCKSL1 signaling cascade might be a potential target for eliminating liver TICs in the management of liver cancer.

Olivero C, Morgan H, Patel GK
Identification of Human Cutaneous Squamous Cell Carcinoma Cancer Stem Cells.
Methods Mol Biol. 2019; 1879:415-433 [PubMed] Related Publications
Epithelia are under constant threat from environmental carcinogens and none more so than squamous epithelia, which form the outermost linings of our bodies. Hence malignancies of squamous epithelia are collectively the most common cancer type and with the highest mortality, despite a constant cell turnover and only relatively rare long-lived adult tissue stem cells. Genetic analysis from SCC whole genome sequencing reveals commonality in mutated genes, despite various etiological factors. Most SCC types have been shown to exhibit hierarchical growth, in which a high frequency of cancer stem cells is associated with poor prognosis. For human cutaneous SCC (cSCC), we have shown that cancer stem cells express CD133 and that this population can recreate tumor heterogeneity in a novel in vivo model. CD133+ cSCC cells is small subset of tumor cells (~1%) in the outer layer of cSCC that are highly enriched for tumor-initiating capacity (TIC) (~1/400) compared to unsorted cSCC cells (~1/10

Angelousi A, Kassi E, Nasiri-Ansari N, et al.
Clock genes alterations and endocrine disorders.
Eur J Clin Invest. 2018; 48(6):e12927 [PubMed] Related Publications
BACKGROUND: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.
DESIGN: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.
RESULTS: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.
CONCLUSIONS: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.

Fu X, Zhu X, Qin F, et al.
Linc00210 drives Wnt/β-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner.
Mol Cancer. 2018; 17(1):73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiation properties, accounting for tumor initiation, metastasis and drug resistance. Long noncoding RNAs are involved in many physiological and pathological processes, including tumorigenesis. DNA copy number alterations (CNA) participate in tumor formation and progression, while the CNA of lncRNAs and their roles are largely unknown.
METHODS: LncRNA CNA was determined by microarray analyses, realtime PCR and DNA FISH. Liver TICs were enriched by surface marker CD133 and oncosphere formation. TIC self-renewal was analyzed by oncosphere formation, tumor initiation and propagation. CRISPRi and ASO were used for lncRNA loss of function. RNA pulldown, western blot and double FISH were used to identify the interaction between lncRNA and CTNNBIP1.
RESULTS: Using transcriptome microarray analysis, we identified a frequently amplified long noncoding RNA in liver cancer termed linc00210, which was highly expressed in liver cancer and liver TICs. Linc00210 copy number gain is associated with its high expression in liver cancer and liver TICs. Linc00210 promoted self-renewal and tumor initiating capacity of liver TICs through Wnt/β-catenin signaling. Linc00210 interacted with CTNNBIP1 and blocked its inhibitory role in Wnt/β-catenin activation. Linc00210 silencing cells showed enhanced interaction of β-catenin and CTNNBIP1, and impaired interaction of β-catenin and TCF/LEF components. We also confirmed linc00210 copy number gain using primary hepatocellular carcinoma (HCC) samples, and found the correlation between linc00210 CNA and Wnt/β-catenin activation. Of interest, linc00210, CTNNBIP1 and Wnt/β-catenin signaling targeting can efficiently inhibit tumor growth and progression, and liver TIC propagation.
CONCLUSION: With copy-number gain in liver TICs, linc00210 is highly expressed along with liver tumorigenesis. Linc00210 drives the self-renewal and propagation of liver TICs through activating Wnt/β-catenin signaling. Linc00210 interacts with CTNNBIP1 and blocks the combination between CTNNBIP1 and β-catenin, driving the activation of Wnt/β-catenin signaling. Linc00210-CTNNBIP1-Wnt/β-catenin axis can be targeted for liver TIC elimination.

Chen Z, Gao Y, Yao L, et al.
LncFZD6 initiates Wnt/β-catenin and liver TIC self-renewal through BRG1-mediated FZD6 transcriptional activation.
Oncogene. 2018; 37(23):3098-3112 [PubMed] Free Access to Full Article Related Publications
Liver tumor-initiating cells (TICs), the drivers for liver tumorigenesis, accounts for liver tumor initiation, metastasis, drug resistance and relapse. Wnt/β-catenin signaling pathway emerges as a critical modulator in liver TIC self-renewal. However, the molecular mechanism of Wnt/β-catenin initiation in liver tumorigenesis and liver TICs is still elusive. Here, we examined the expression pattern of 10 Wnt receptors (FZD1-FZD10), and found only FZD6 is overexpressed along with liver tumorigenesis. What's more, a divergent lncRNA of FZD6, termed lncFZD6, is also highly expressed in liver cancer and liver TICs. LncFZD6 drives liver TIC self-renewal and tumor initiation capacity through FZD6-dependent manner. LncFZD6 interacts with BRG1-embedded SWI/SNF complex and recruits it to FZD6 promoter, and thus drives the transcriptional initiation of FZD6 by chromatin remodeling. WNT5A, a ligand of FZD6, is highly expressed in liver non-TICs and drives the self-renewal of liver TICs through lncFZD6-BRG1-FZD6-dependent manner. Through FZD6 transcriptional regulation in cis, lncFZD6 activates Wnt/β-catenin signaling in liver TICs. LncFZD6-BRG1-Wnt5A/β-catenin pathway can serve as a target for liver TIC elimination. Altogether, lncFZD6 promotes Wnt/β-catenin activation and liver TIC self-renewal through BRG1-dependent FZD6 expression.

Cheng BY, Lau EY, Leung HW, et al.
IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma.
Cancer Res. 2018; 78(9):2332-2342 [PubMed] Related Publications
Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment

Mocellin S, Tropea S, Benna C, Rossi CR
Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.
BMC Med. 2018; 16(1):20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).
METHODS: Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n = 15,748; controls, n = 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n = 14,160; controls, n = 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n = 12,160; controls, n = 16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.
RESULTS: We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value = 1.9 × 10
CONCLUSIONS: Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Ferrero H, Díaz-Gimeno P, Sebastián-León P, et al.
Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment.
Reproduction. 2018; 155(4):373-381 [PubMed] Related Publications
Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2. Here, LGCs from non-PCOS and PCOS patients were cultured with hCG in the absence/presence of Cb2 (

Jiang W, Zhao S, Shen J, et al.
The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance.
Cell Death Dis. 2018; 9(2):149 [PubMed] Free Access to Full Article Related Publications
Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3'-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies. Moreover, we found that YY1 transcriptionally activated miR-135b and formed a 'miR-135b-BMAL1-YY1' loop, which holds significant predictive and prognostic value for patients with PC. Thus, our work has identified a novel signalling loop that mediates pancreatic clock disruption as an important mechanism of PC progression and chemoresistance.

Timaner M, Letko-Khait N, Kotsofruk R, et al.
Therapy-Educated Mesenchymal Stem Cells Enrich for Tumor-Initiating Cells.
Cancer Res. 2018; 78(5):1253-1265 [PubMed] Free Access to Full Article Related Publications
Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs

Dierickx P, Van Laake LW, Geijsen N
Circadian clocks: from stem cells to tissue homeostasis and regeneration.
EMBO Rep. 2018; 19(1):18-28 [PubMed] Free Access to Full Article Related Publications
The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep-to-wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock-controlled output genes, which results in tissue-specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.

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