Gene Summary

Gene:KRT1; keratin 1
Aliases: K1, CK1, EHK, EHK1, EPPK, KRT1A, NEPPK
Summary:The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the spinous and granular layers of the epidermis with family member KRT10 and mutations in these genes have been associated with bullous congenital ichthyosiform erythroderma. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:keratin, type II cytoskeletal 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (14)
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.

  • Hyperkeratosis, Epidermolytic
  • Mutation
  • rho-Associated Kinases
  • Staphylococcal Scalded Skin Syndrome
  • Cell Differentiation
  • Mice, Transgenic
  • Signal Transduction
  • Neoplasm Invasiveness
  • Promoter Regions
  • RNA Splice Sites
  • Neoplastic Cell Transformation
  • Phenotype
  • Disease Models, Animal
  • TNF
  • Cancer Gene Expression Regulation
  • Hyperplasia
  • Tetradecanoylphorbol Acetate
  • Chromosome 12
  • DNA Mutational Analysis
  • Cell Proliferation
  • DNA-Binding Proteins
  • Keratins
  • Keratin-14
  • Papilloma
  • Membrane Proteins
  • Biomarkers, Tumor
  • Wnt-5a Protein
  • beta Catenin
  • Keratin-1
  • Squamous Cell Carcinoma
  • Skin Cancer
  • Keratin-10
  • Trans-Activators
  • Keratinocytes
  • Keratin-5
  • Cervical Cancer
  • Carcinogens
  • Epidermis
  • Gene Expression
  • Keratin-15
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: KRT1 (cancer-related)

Xu P, Ianes C, Gärtner F, et al.
Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D).
Gene. 2019; 715:144005 [PubMed] Related Publications
Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stress-induced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.

Zhang Z, Zhang W, Mao J, et al.
miR-186-5p Functions as a Tumor Suppressor in Human Osteosarcoma by Targeting FOXK1.
Cell Physiol Biochem. 2019; 52(3):553-564 [PubMed] Related Publications
BACKGROUND/AIMS: Aberrantly expressed miRNAs play a vital role in the development of some cancers, such as human osteosarcoma (OS). However, the detailed molecular mechanisms underlying miR-186-5p-involved osteosarcoma are unclear.
METHODS: qRT-PCR and western blot analysis were employed to measure the expressions of miR-186-5p and forkhead box k1 (FOXK1). CCK-8 assay evaluated the effect of miR-186-5p and FOXK1 on cell proliferation. Transwell assay confirmed cell migration and invasion. Eventually, the dual-luciferase reporter assay validated 3'-untranslated region (3'-UTR) of FOXK1 as a direct target of miR-186-5p.
RESULTS: Down-regulation of miR-186-5p was identified in OS tissues and cell lines, and negatively correlated with distant metastasis, Enneking stage and poor 5-year prognosis as well as the expression of forkhead box k1 (FOXK1) protein. Further assays demonstrated that miR-186-5p overexpression had inhibitory effects on in-vitro cell proliferation, cell cycle, and in-vivo tumor growth. miR-186-5p overexpression also inhibited the epithelial-tomesenchymal transition (EMT), migration and invasion of OS cells. Importantly, miR-186-5p directly targeted FOXK1 3'-UTR and negatively regulated its expression. Silencing of FOXK1 expression enhanced the inhibitory effects of miR-186-5p on OS cell proliferation, migration and invasion.
CONCLUSION: These findings highlighted miR-186-5p as a tumor suppressor in the regulation of progression and metastatic potential of OS, and may benefit the development of therapies targeting miR-186-5p in patients with OS.

Matossian MD, Burks HE, Elliott S, et al.
Drug resistance profiling of a new triple negative breast cancer patient-derived xenograft model.
BMC Cancer. 2019; 19(1):205 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC) represents an aggressive subtype with limited therapeutic options. Experimental preclinical models that recapitulate their tumors of origin can accelerate target identification, thereby potentially improving therapeutic efficacy. Patient-derived xenografts (PDXs), due to their genomic and transcriptomic fidelity to the tumors from which they are derived, are poised to improve the preclinical testing of drug-target combinations in translational models. Despite the previous development of breast and TNBC PDX models, those derived from patients with demonstrated health-disparities are lacking.
METHODS: We use an aggressive TNBC PDX model propagated in SCID/Beige mice that was established from an African-American woman, TU-BcX-2 K1, and assess its metastatic potential and drug sensitivities under distinct in vitro conditions. Cellular derivatives of the primary tumor or the PDX were grown in 2D culture conditions or grown in mammospheres 3D culture. Flow cytometry and fluorescence staining was used to quantify cancer stem cell-like populations. qRT-PCR was used to describe the mesenchymal gene signature of the tumor. The sensitivity of TU-BcX-2 K1-derived cells to anti-neoplastic oncology drugs was compared in adherent cells and mammospheres. Drug response was evaluated using a live/dead staining kit and crystal violet staining.
RESULTS: TU-BcX-2 K1 has a low propensity for metastasis, reflects a mesenchymal state, and contains a large burden of cancer stem cells. We show that TU-BcX-2 K1 cells have differential responses to cytotoxic and targeted therapies in 2D compared to 3D culture conditions insofar as several drug classes conferred sensitivity in 2D but not in 3D culture, or cells grown as mammospheres.
CONCLUSIONS: Here we introduce a new TNBC PDX model and demonstrate the differences in evaluating drug sensitivity in adherent cells compared to mammosphere, or suspension, culture.

Rose TM, Bruce AG, Barcy S, et al.
Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter.
PLoS Pathog. 2018; 14(12):e1007441 [PubMed] Free Access to Full Article Related Publications
KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV transcriptome. Phylogenetic analysis of ORF75 sequences from 23 tumors revealed 6 distinct genetic clusters with KSHV strains exhibiting M, N or P alleles. RNA reads mapping to specific unique coding sequence (UCDS) features were quantitated using a gene feature file previously developed to globally analyze and quantitate KSHV transcription in infected endothelial cells. A pattern of high level expression was detected in the KSHV latency region that was common to all KS tumors. The clear majority of transcription was derived from the downstream latency transcript promoter P3(LTd) flanking ORF72, with little evidence of transcription from the P1(LTc) latency promoter, which is constitutive in KSHV-infected lymphomas and tissue-culture cells. RNAseq data provided evidence of alternate P3(LTd) transcript editing, splicing and termination resulting in multiple gene products, with 90% of the P3(LTd) transcripts spliced to release the intronic source of the microRNAs K1-9 and 11. The spliced transcripts encode a regulatory uORF upstream of Kaposin A with alterations in intervening repeat sequences yielding novel or deleted Kaposin B/C-like sequences. Hierarchical clustering and PCA analysis of KSHV transcripts revealed three clusters of tumors with different latent and lytic gene expression profiles. Paradoxically, tumors with a latent phenotype had high levels of total KSHV transcription, while tumors with a lytic phenotype had low levels of total KSHV transcription. Morphologically distinct KS tumors from the same individual showed similar KSHV gene expression profiles suggesting that the tumor microenvironment and host response play important roles in the activation level of KSHV within the infected tumor cells.

Yi T, Zhou X, Sang K, et al.
MicroRNA-1270 modulates papillary thyroid cancer cell development by regulating SCAI.
Biomed Pharmacother. 2019; 109:2357-2364 [PubMed] Related Publications
PURPOSE: We intended to evaluate expression and mechanisms of human microRNA 1270 (hsa-miR-1270) in papillary thyroid cancer (PTC).
METHODS: In PTC cell lines and human PTC tumors, hsa-miR-1270 expressions were evaluated by qRT-PCR. Hsa-miR-1270 was downregulated in TPC1 and K1 cells via lentiviral transduction. Its effects on PTC cancer cell proliferation, migration and in vivo transplantation were assessed, respectively. Potential targeting of hsa-miR-1270 on downstream gene, Suppressor Of Cancer Cell Invasion (SCAI), was assessed. In hsa-miR-1270-downregulated PTC cells, SCAI was further downregulated to examine its associating role in hsa-miR-1270-mediated regulation on cancer cell proliferation and migration.
RESULTS: Hsa-miR-1270 was aberrantly upregulated in PTC cell lines and human PTC tumors. In TPC1 and K1 cells, lentivirus-mediated hsa-miR-1270 downregulation suppressed cancer cell proliferation, migration and in vivo transplantation. Hsa-miR-1270 binds SCAI and inversely regulated SCAI gene expression in PTC cells. SCAI downregulation removed the suppressing effects of hsa-miR-1270 downregulation in human PTC cells.
CONCLUSION: Hsa-miR-1270 downregulation may suppress human PTC cell development both in vitro and in vivo. The regulatory mechanism of hsa-miR-1270 in PTC may be primarily associated with SCAI.

Hoggarth ZE, Osowski DB, Freeberg BA, et al.
The urothelial cell line UROtsa transformed by arsenite and cadmium display basal characteristics associated with muscle invasive urothelial cancers.
PLoS One. 2018; 13(12):e0207877 [PubMed] Free Access to Full Article Related Publications
Muscle invasive urothelial carcinomas are divided into various molecular subtypes with basal and luminal subtypes being the prominent ones. The basal muscle-invasive urothelial carcinomas are generally more aggressive at presentation and significantly enriched with squamous features. Our laboratory has developed an in-vitro model of urothelial cancer by transforming the immortalized cell line UROtsa with arsenite (As3+) and cadmium (Cd2+). In this study, we characterized the tumors formed by these transformed cell lines as more basal-like based on their gene expression patterns with increased expression of KRT1, KRT5, KRT6, KRT14, KRT16, KRT17 and CD44. In addition, histological examination of these tumor transplants showed squamous features enriched in basal muscle invasive urothelial carcinomas. The expression of these genes increased in the transformed cell lines as well as in the urospheres, which are putative cancer initiating cells/stem cells derived from the cell lines. There was also increased expression of these genes in the urospheres derived from the parent UROtsa cell line. Thus, our data shows that the As3+ and Cd2+-transformed cell lines and their derived tumor transplants have gene expression profiles similar to the basal subtype of muscle invasive bladder carcinomas with tumors having enriched squamous features. The increased expression of basal markers in the urospheres suggests that stem cells may be involved in the development of squamous differentiation seen in some of the muscle invasive bladder carcinomas.

Chen LL, Gao GX, Shen FX, et al.
SDC4 Gene Silencing Favors Human Papillary Thyroid Carcinoma Cell Apoptosis and Inhibits Epithelial Mesenchymal Transition
Mol Cells. 2018; 41(9):853-867 [PubMed] Free Access to Full Article Related Publications
As the most common type of endocrine malignancy, papillary thyroid cancer (PTC) accounts for 85-90% of all thyroid cancers. In this study, we presented the hypothesis that SDC4 gene silencing could effectively attenuate epithelial mesenchymal transition (EMT), and promote cell apoptosis

Etta EM, Alayande DP, Mavhandu-Ramarumo LG, et al.
HHV-8 Seroprevalence and Genotype Distribution in Africa, 1998⁻2017: A Systematic Review.
Viruses. 2018; 10(9) [PubMed] Free Access to Full Article Related Publications
Human herpes virus type 8 (HHV-8) is the causative agent of Kaposi's sarcoma (KS). We systematically reviewed literature published between 1998 and 2017, according to the PRISMA guidelines, to understand the distribution of HHV-8 infection in Africa. More than two-thirds (64%) of studies reported on seroprevalence and 29.3% on genotypes; 9.5% were on both seroprevalence and genotypes. About 45% of African countries had data on HHV-8 seroprevalence exclusively, and more than half (53%) had data on either seroprevalence or genotypes. Almost half (47%) of the countries had no data on HHV-8 infection. There was high heterogeneity in the types of tests and interpretation algorithms used in determining HHV-8 seropositivity across the different studies. Generally, seroprevalence ranged from 2.0% in a group of young children in Eritrea to 100% in a small group of individuals with KS in Central African Republic, and in a larger group of individuals with KS in Morocco. Approximately 16% of studies reported on children. Difference in seroprevalence across the African regions was not significant (95% CI, χ² = 0.86;

Yonekura S, Itoh M, Shiratori E, et al.
FOXP3 knockdown inhibits the proliferation and reduces NOTCH1 expression of T cell acute lymphoblastic leukemia cells.
BMC Res Notes. 2018; 11(1):582 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Forkhead box P3 (FOXP3) is a master transcriptional factor of regulatory T-cells (Tregs). Recent studies have shown that FOXP3 is associated with growth inhibition of cancer cells. However, the role of FOXP3 in acute T-lymphoblastic leukemia (T-ALL) cells is not known. It was also reported that NOTCH signaling promoted the expression of FOXP3 in Tregs. However, the effect of FOXP3 on NOTCH expression in T-ALL cells is little known. Therefore, we examined the effect of FOXP3 knockdown on the proliferation of T-ALL cells and NOTCH1 signaling.
RESULTS: Two T-ALL cell lines Jurkat and KOPT-K1, harboring activating NOTCH1 mutations, were transfected with small interfering RNA against FOXP3. Cell growth was assessed with a colorimetric assay and morphology was observed under a microscope. FOXP3 knockdown significantly reduced cell growth and induced morphological changes suggesting apoptosis. Quantitative polymerase chain reaction revealed that FOXP3 knockdown caused the downregulation of mRNA expression of NOTCH1 and HES1. These findings suggest that FOXP3 supports the growth of T-ALL cells although this can not be generalized because we examined only two cell lines. The observed growth suppression can be partly due to the downregulation of NOTCH1 signaling. FOXP3 may be a potential therapeutic target in T-ALL.

Su Z, Song J, Wang Z, et al.
Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner.
Proc Natl Acad Sci U S A. 2018; 115(32):E7522-E7531 [PubMed] Free Access to Full Article Related Publications
The tumor promoter 12-

Liu H, Wang X, Feng B, et al.
Golgi phosphoprotein 3 (GOLPH3) promotes hepatocellular carcinoma progression by activating mTOR signaling pathway.
BMC Cancer. 2018; 18(1):661 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite new technologies in diagnosis and treatment, the incidence and mortality of HCC continue rising. And its pathogenesis is still unclear. As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis of HCC. This study aimed to explore the exact oncogenic mechanism of GOLPH3 and provide a novel diagnose biomarker and therapeutic strategy for patients with HCC.
METHODS: Firstly, the expression of GOLPH3 was detected in the HCC tissue specimens and HCC cell lines. Secondly, RNA interference was used for GOLPH3 gene inhibition. Thirdly, cell proliferation was analyzed by MTT; cell apoptosis was analyzed by Annexin-V/PI staining, Hoechst 33,342 staining and caspase 3/7 activity assay. Fourthly, xenograft tumor model was used to study the function of GOLPH3 in tumor growth in vivo. Finally, western blotting and immunohistochemistry were used to investigate the role of GOLHP3 in the mTOR signaling pathway.
RESULTS: Data showed that the mRNA and protein expression of GOLPH3 were up-regulated in HCC tumor tissue and cell lines compared with those of control (P < 0.05). Correlation analyses showed that GOLPH3 expression was positively correlated with serum alpha-fetoprotein level (AFP, P = 0.006). Knockdown GOLPH3 expression inhibited proliferation and promoted apoptosis in HCC cell lines. What's more, knockdown GOLPH3 expression led to tumor growth restriction in xenograft tumor model. The expression of phosphorylated mTOR, AKT and S6 K1 were significantly higher in HCC tumor tissue and cell lines compared with those in normal liver tissues (p < 0.05). While the phosphorylated mTOR, AKT and S6 K1 were much lower when diminished GOLPH3 expression in HCC cell lines both in vitro and in vivo.
CONCLUSION: The current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway. GOLPH3 is a promising diagnose biomarker and therapeutic target for HCC. Our study may provide a scientific basis for developing effective approaches to treat the HCC patients with GOLPH3 overexpression.

Huang Y, Yu S, Cao S, et al.
MicroRNA-222 Promotes Invasion and Metastasis of Papillary Thyroid Cancer Through Targeting Protein Phosphatase 2 Regulatory Subunit B Alpha Expression.
Thyroid. 2018; 28(9):1162-1173 [PubMed] Related Publications
BACKGROUND: Increasing evidence indicates that microRNA dysfunction is involved in the pathogenesis and progression of cancer. MicroRNA-222 (miR-222) is upregulated in papillary thyroid carcinoma (PTC). However, the role of miR-222 in invasion and metastasis of PTC remains unknown. This study investigated the function of miR-222 and its underlying mechanism in the progression of PTC.
METHODS: The expression of miR-222 was detected by quantitative reverse transcription polymerase chain reaction, and its correlation with various clinical characteristics was analyzed. The role of miR-222 in PTC cell migration ability was assessed with Transwell
RESULTS: This study confirmed that miR-222 was upregulated in PTC tissues compared to adjacent thyroid tissues and that it correlated with aggressive cancer phenotypes. The results indicate that ectopic miR-222 enhanced cell migration and invasion of thyroid cancer cells in vitro and distant pulmonary metastases in vivo. Protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), a tumor suppressor, was identified as a direct target of miR-222 through the 3'-UTR of PPP2R2A. Restoring PPP2R2A expression led to the attenuation of migration and invasion in miR-222-overexpressing thyroid cancer cells. Moreover, we found that miR-222 promoted invasion and metastasis partly through the AKT signaling pathway.
CONCLUSIONS: Taken together, the results suggest that miR-222 promotes tumor invasion and metastasis in thyroid cancer by targeting PPP2R2A. Thus, miR-222 could serve as a potential diagnostic biomarker, as well as an attractive therapeutic tool for thyroid cancer.

Tuong ZK, Noske K, Kuo P, et al.
Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions.
Papillomavirus Res. 2018; 5:6-20 [PubMed] Free Access to Full Article Related Publications
Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines.

Huang X, Xiang L, Li Y, et al.
Snail/FOXK1/Cyr61 Signaling Axis Regulates the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.
Cell Physiol Biochem. 2018; 47(2):590-603 [PubMed] Related Publications
BACKGROUND/AIMS: Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear.
METHODS: We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo.
RESULTS: A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced "CRC cell" migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis.
CONCLUSIONS: The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.

Yamada S, Itai S, Nakamura T, et al.
Monoclonal Antibody L
Monoclon Antib Immunodiagn Immunother. 2018; 37(2):110-115 [PubMed] Related Publications
Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells. It is also expressed in several tumor cells such as melanoma and lung cancer cells. A strong correlation has been reported between human PD-L1 (hPD-L1) expression in tumor cells and negative prognosis in cancer patients. Here, a novel anti-hPD-L1 monoclonal antibody (mAb) L

Yue B, Liu C, Sun H, et al.
A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/β-Catenin Signaling Promotes Metastasis of Colon Cancer.
Mol Ther. 2018; 26(5):1287-1298 [PubMed] Free Access to Full Article Related Publications
We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic β-catenin impeded casein kinase 1 (CK1)-induced β-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, β-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear β-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with β-catenin, and the positive feed-forward circuit of CYTOR-β-catenin might be a useful therapeutic target in antimetastatic strategy.

Srivastava SS, Alam H, Patil SJ, et al.
Keratin 5/14‑mediated cell differentiation and transformation are regulated by TAp63 and Notch‑1 in oral squamous cell carcinoma‑derived cells.
Oncol Rep. 2018; 39(5):2393-2401 [PubMed] Related Publications
Keratins 5/14 (K5/14) are intermediate filament proteins expressed in the basal layer of stratified epithelial cells and are known targets of p63. Previous research in our laboratory showed that upon K5/14 downregulation in oral squamous cell carcinoma (OSCC)‑derived cells, there was an increase in intracellular Notch‑1 levels and differentiation markers such as involucrin, keratin 1 and a decrease in tumorigenic potential in vivo. However, the molecules involved in the K14 regulated cell differentiation and transformation are not known to date. In order to understand the possible role of TAp63, we downregulated TAp63 in a K14‑knockdown background. We observed that there was a decrease in the expression of Notch‑1. Expression levels of differentiation markers such as involucrin, K1, loricrin and filaggrin were also decreased. Furthermore, TAp63 downregulation led to an increase in invasion, migration and in vivo tumorigenic potential of these cells. We observed a decrease in β‑catenin signaling in K14‑downregulated cells. Notably, when TAp63 was downregulated in K14‑knockdown cells, there was increase in non‑phospho β‑catenin levels. Hence, this study indicates that TAp63 plays an important role in K14‑downregulated cells possibly by regulating the Notch‑1 expression. K14 regulates the expression of TAp63 which in turn regulates expression of Notch‑1. The present study is a step forward in our quest to understand the functional significance of molecules that regulate the process of differentiation and tumorigenesis in stratified epithelial cells.

Liao T, Wang YJ, Hu JQ, et al.
Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro.
Oncol Rep. 2018; 39(5):2185-2192 [PubMed] Related Publications
KMT5A (known as PR-Set7/9, SETD8 and SET8), a member of the SET domain containing methyltransferase family specifically targeting H4K20 for methylation, has been implicated in multiple biological processes. In the present study, we identified that KMT5A was elevated in 50 pairs of papillary thyroid cancer tissue samples and in cell lines K1 and TPC-1 by qRT-PCR and western blotting, as well as by immunohistochemical staining. CCK-8 assay and flow cytometric analysis revealed that inhibition of KMT5A attenuated proliferation and induced apoptosis. Transwell assays revealed that cell migration and invasion were suppressed in KMT5A-knockdown cells. Moreover, the inhibition of KMT5A arrested the cell cycle in the G1/S phase of papillary thyroid cancer cells. The TCGA data revealed that elevated KMT5A expression was significantly correlated with extrathyroidal extension, lymph node metastasis and advanced pathological stage of papillary thyroid cancer. Furthermore, we observed that inhibition of KMT5A suppressed the expression of SREBP1, SCD, FASN and ACC, key molecules involved in lipid metabolism and decreased the level of malondialdehyde in papillary thyroid cancer cells. In conclusion, KMT5A may be a novel oncogenic factor, specifically a regulator for lipid metabolism in papillary thyroid carcinoma.

Richter J, Kretz AL, Lemke J, et al.
CK1α overexpression correlates with poor survival in colorectal cancer.
BMC Cancer. 2018; 18(1):140 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is the fourth leading cause of cancer related deaths worldwide and prognosis in advanced tumor stage still remains poor. Since CK1 isoforms have been reported to be deregulated in several tumor entities CK1 has emerged as a novel drug target in cancer therapy. In this study we set out to investigate whether CK1α might have the potential to serve as prognostic marker.
METHODS: CK1α RNA and protein expression levels in healthy and tumor tissue of CRC patients were analyzed using quantitative real-time PCR and Western Blot analysis, respectively. Prognostic relevance was investigated by correlating obtained CK1α expression levels with patients' survival rate generating Kaplan-Meier survival plots.
RESULTS: It could be shown that CK1α is overexpressed in colorectal tumor tissue compared to normal tissue and CK1α overexpression in tumor tissue correlates with poor survival in CRC patients. Results become more significant when only considering patients with high-grade tumors, as well as patients assigned to UICC II and UICC III stage. Furthermore, Cox regression analysis revealed that CK1α is an independent prognostic factor. In addition, tumors expressing decreased levels of the kinase reveal positive effects on overall survival when localized in the right colon compared to those in the left side.
CONCLUSION: In summary, this study provides evidence for the first time that CK1α RNA levels might serve as prognostic marker for CRC.

Wang D, Lu G, Shao Y, Xu D
MiR-182 promotes prostate cancer progression through activating Wnt/β-catenin signal pathway.
Biomed Pharmacother. 2018; 99:334-339 [PubMed] Related Publications
Although prostate cancer can be surgical excised and effectively treated by androgen-deprivation therapy, radiotherapy, or chemotherapy, management of patients with advanced or drug-resistance prostate cancer stills remains a big trouble. Accumulated evidence indicated that miR-182 and Wnt/β-catenin function as tumor oncogene in the progression of a variety of tumors. However, little is known about how miR-182 regulates β-catenin signal molecular and impacts on the tumorigenesis of human prostate cancer. In this study, employing the analyses of qRT-PCR, we found that prostate cancer tissues expressed much more miR-182 than non-cancer tissues did. In vitro studies revealed that overexpression of miR-182 promoted cell proliferation, colony formation, migration, invasion and inhibited cell apoptosis; in vivo results demonstrated that silencing of miR-182 mediated by inhibitor dramatically reduced prostate cancer xenograft tumor growth. Importantly, through western blotting analysis, we identified that miR-182 dramatically activated Wnt/β-catenin pathway by targeting multiple negative regulators of Wnt/β-catenin signaling, including GSK-3β, APC, CK1 and Axin. Besides, we observed the elevated levels of c-myc and Cyclin D1 when PC-3 and LNCap cells were up-regulated miR-182. Our findings indicate that miR-182 acts as one of oncogenic factor in the progression of prostate cancer by recruiting a mechanism of aberrant activation of Wnt/β-catenin signaling.

Janovska P, Verner J, Kohoutek J, et al.
Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia.
Blood. 2018; 131(11):1206-1218 [PubMed] Related Publications
Casein kinase 1δ/ε (CK1δ/ε) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1δ/ε inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.

Li M, Jin C, Xu M, et al.
Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling.
Cell Commun Signal. 2017; 15(1):52 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear.
METHODS: ATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays.
RESULTS: Here, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells.
CONCLUSION: Taken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling.

Khowal S, Naqvi SH, Monga S, et al.
Assessment of cellular and serum proteome from tongue squamous cell carcinoma patient lacking addictive proclivities for tobacco, betel nut, and alcohol: Case study.
J Cell Biochem. 2018; 119(7):5186-5221 [PubMed] Related Publications
The intriguing molecular pathways involved in oral carcinogenesis are still ambiguous. The oral squamous cell carcinoma (OSCC) ranks as the most common type constituting more than 90% of the globally diagnosed oral cancers cases. The elevation in the OSCC incidence rate during past 10 years has an alarming impression on human healthcare. The major challenges associated with OSCC include delayed diagnosis, high metastatic rates, and low 5-year survival rates. The present work foundations on reverse genetic strategy and involves the identification of genes showing expressional variability in an OSCC case lacking addictive proclivities for tobacco, betel nut, and/or alcohol, major etiologies. The expression modulations in the identified genes were analyzed in 16 patients comprising oral pre-cancer and cancer histo-pathologies. The genes SCCA1 and KRT1 were found to down regulate while DNAJC13, GIPC2, MRPL17, IG-Vreg, SSFA2, and UPF0415 upregulated in the oral pre-cancer and cancer pathologies, implicating the genes as crucial players in oral carcinogenesis.

Dolde C, Bischof J, Grüter S, et al.
A CK1 FRET biosensor reveals that DDX3X is an essential activator of CK1ε.
J Cell Sci. 2018; 131(1) [PubMed] Free Access to Full Article Related Publications
Casein kinase 1 (CK1) plays central roles in various signal transduction pathways and performs many cellular activities. For many years CK1 was thought to act independently of modulatory subunits and in a constitutive manner. Recently, DEAD box RNA helicases, in particular DEAD box RNA helicase 3 X-linked (DDX3X), were found to stimulate CK1 activity

Huebner D, Rieger C, Bergmann R, et al.
An orthotopic xenograft model for high-risk non-muscle invasive bladder cancer in mice: influence of mouse strain, tumor cell count, dwell time and bladder pretreatment.
BMC Cancer. 2017; 17(1):790 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging.
METHODS: Luciferase-transduced UM-UC-3
RESULTS: Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration - both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 10
CONCLUSIONS: With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.

Gieldon L, Masjkur JR, Richter S, et al.
Next-generation panel sequencing identifies
Eur J Endocrinol. 2018; 178(2):K1-K9 [PubMed] Related Publications
OBJECTIVE: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with
DESIGN: We performed genetic analysis of known tumor predisposition genes, including
METHODS: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing.
RESULTS: Within our cohort, three patients, who were identified to carry pathogenic
CONCLUSIONS: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the

Abere B, Mamo TM, Hartmann S, et al.
The Kaposi's sarcoma-associated herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target.
PLoS Pathog. 2017; 13(9):e1006639 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of the highly vascularized tumor Kaposi's sarcoma (KS), which is characterized by proliferating spindle cells of endothelial origin, extensive neo-angiogenesis and inflammatory infiltrates. The KSHV K15 protein contributes to the angiogenic and invasive properties of KSHV-infected endothelial cells. Here, we asked whether K15 could also play a role in KSHV lytic replication. Deletion of the K15 gene from the viral genome or its depletion by siRNA lead to reduced virus reactivation, as evidenced by the decreased expression levels of KSHV lytic proteins RTA, K-bZIP, ORF 45 and K8.1 as well as reduced release of infectious virus. Similar results were found for a K1 deletion virus. Deleting either K15 or K1 from the viral genome also compromised the ability of KSHV to activate PLCγ1, Erk1/2 and Akt1. In infected primary lymphatic endothelial (LEC-rKSHV) cells, which have previously been shown to spontaneously display a viral lytic transcription pattern, transfection of siRNA against K15, but not K1, abolished viral lytic replication as well as KSHV-induced spindle cell formation. Using a newly generated monoclonal antibody to K15, we found an abundant K15 protein expression in KS tumor biopsies obtained from HIV positive patients, emphasizing the physiological relevance of our findings. Finally, we used a dominant negative inhibitor of the K15-PLCγ1 interaction to establish proof of principle that pharmacological intervention with K15-dependent pathways may represent a novel approach to block KSHV reactivation and thereby its pathogenesis.

Okuhashi Y, Itoh M, Tohda S
Hedgehog Stimulation Suppresses Clonogenicity and Activates NOTCH Signalling in T-lymphoblastic Leukaemia Jurkat Cells.
Anticancer Res. 2017; 37(9):5005-5009 [PubMed] Related Publications
BACKGROUND/AIM: Hedgehog (HH) and NOTCH pathways are involved in the regulation of cancer stem cells and haematopoietic malignancies. However, the effects of HH stimulation on cell growth and NOTCH signalling in acute T-lymphoblastic leukaemia (T-ALL) cells have not been elucidated.
MATERIALS AND METHODS: Two T-ALL cell lines, Jurkat and KOPT-K1 harbouring activating NOTCH1 mutations, were cultured with recombinant Sonic (S) HH and analysed for proliferation, colony formation, and expression of NOTCH-regulated genes and proteins.
RESULTS: SHH stimulation did not affect cell growth but suppressed colony formation, increased the levels of cleaved NOTCH1 fragment characteristic for NOTCH1 activation, and upregulated mRNA expression of HES1, while decreasing that of MYC in Jurkat cells. However, no such effects were observed in KOPT-K1 cells.
CONCLUSION: Our results indicate that SHH stimulation activates NOTCH signalling in Jurkat cells, thus disclosing a novel relationship between HH and NOTCH pathways.

Kolanowska M, Wójcicka A, Kubiak A, et al.
Functional analysis of a novel, thyroglobulin-embedded microRNA gene deregulated in papillary thyroid carcinoma.
Sci Rep. 2017; 7(1):9942 [PubMed] Free Access to Full Article Related Publications
MicroRNAs, non-coding regulators of gene expression, are known culprits of thyroid cancer. Using next-generation sequencing, we identified a novel microRNA gene, encoded within an important thyroid regulator - thyroglobulin, and analyzed its functionality in the thyroid gland. In vitro and in silico analyses proved that the novel miR-TG is processed from the precursor, and co-expressed with thyroglobulin. Both genes are specific for thyroid tissue and downregulated in papillary thyroid carcinoma by 44% (p = 0.04) and 48% (p = 0.001), respectively. Putative target genes for miR-TG were identified using in silico tools, which pinpointed MAP4K4, an oncogene upregulated in thyroid cancer. Analysis of transcriptome by RNA-seq revealed that overexpression of miR-TG in PTC-derived cell line led to downregulation of several genes, including MAP4K4 (fold change 0,82; p = 0.036). The finding was confirmed by SQ-PCR (fold change 071; p = 0.004). Direct interaction between miR-TG and MAP4K4 was confirmed in the luciferase assay (p = 0.0006). Functional studies showed increase proliferation in K1 cell line transfected with miR-TG. We propose that in normal thyroid miR-TG plays a fine-tuning effect on the maintenance of MAPK pathway, inhibiting the expression of miR's target MAP4K4. This regulation is disturbed in cancer due to downregulation of the novel, thyroglobulin-embedded microRNA, characterized in this study.

Hara R, Onizuka M, Matsusita E, et al.
NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib.
Int J Hematol. 2017; 106(5):666-674 [PubMed] Related Publications
A recent study reported that treatment-free remission (TFR) of chronic myeloid leukemia (CML) after dasatinib (Das) treatment was significantly associated with natural killer (NK) cell proliferation in the peripheral blood. However, biomarkers to predict lymphocytosis or successful TFR are not well characterized. In order to clarify individual differences in NK cell responses among patients treated with Das, we retrospectively analyzed the association between polymorphisms in the natural killer group 2D receptor [NKG2D; also known as killer cell lectin like receptor K1 (KLRK1)] gene and clinical outcomes in 31 patients treated with Das as first-line treatment for CML. Patients with the NKG2D HNK1/HNK1 (high-cytotoxic activity-related allele on NKG2D hb-1) haplotype achieved MR4.5 more quickly than those with other haplotypes [hazard ratio (HR) 4.39; 95% confidence interval (CI) 2.75-118.6; P = 0.004]. In addition, NK cells with the NKG2D HNK1 allele exhibited enhanced phosphorylation of vav guanine nucleotide exchange factor 1 (VAV1) at Tyr174. These data suggest that NKG2D gene polymorphisms may represent candidate biomarkers for the prediction of TFR following Das treatment.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. KRT1, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 31 August, 2019     Cancer Genetics Web, Established 1999