Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (9)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HAS2 (cancer-related)
Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin-mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss- and gain-of-function experiments revealed that it regulates CRC malignancy through TGF-β expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF-β signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.
Goldrat O, Van Den Steen G, Gonzalez-Merino E, et al.Letrozole-associated controlled ovarian hyperstimulation in breast cancer patients versus conventional controlled ovarian hyperstimulation in infertile patients: assessment of oocyte quality related biomarkers.
Reprod Biol Endocrinol. 2019; 17(1):3 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Fertility preservation (FP) protocols in case of breast cancer (BC) include mature oocyte cryopreservation following letrozole associated controlled ovarian hyperstimulation (Let-COH). To date, the impact of Let-COH on the follicular microenvironment has been poorly investigated, although a high androgen/estrogen ratio was previously associated with low oocyte quality.
METHODS: In this prospective study, follicular fluid (FF) steroid levels (estradiol, testosterone, progesterone) and cumulus cell (CC) gene expression related to oocyte quality (HAS2, PTGS2, GREM1) were compared between 23 BC patients undergoing Let-COH for FP and 24 infertile patients undergoing conventional COH without letrozole. All patients underwent an antagonist COH cycle, and ovulation was triggered with hCG or GnRHa in both groups.
RESULTS: FF estradiol levels were significantly lower while testosterone levels were significantly higher in the study group compared to controls irrespective of the trigger method. However, estradiol levels increased significantly with GnRHa triggering compared to hCG in the study group (median = 194.5 (95.4-438) vs 64.4 (43.8-152.4) ng/ml, respectively, p < 0.001), but not in the control group (median = 335.5 (177.5-466.7) vs 354 (179-511) ng/ml, respectively). After hCG trigger, Cumulus cell (CC) gene expression was lower in the study group compared to the control group, and difference was significant for PTGS2. Conversely, CC gene expression of PTGS2 and GREM1 was significantly higher in the study group compared to controls when ovulation was triggered with GnRHa.
CONCLUSIONS: Let-COH triggered with hCG may negatively impact oocyte quality. However, ovulation triggering with GnRHa may improve the oocyte microenvironment and cumulus cell genes expression in Let-COH, suggesting a positive impact on oocyte quality in breast cancer patients.
TRIAL REGISTRATION: Clinicaltrials.gov - NCT02661932 , registered 25 January 2016, retrospectively registered.
LncRNA HAND2-AS1 is characterized as a tumor suppressor involved in several types of malignancies, but its role in non-small cell lung cancer (NSCLC) is unknown. Our study was carried out to investigate the involvement of lncRNA HAND2-AS1 in NSCLC. In our study, we observed that levels of HAND2-AS1 were lower in tumor tissues than that in adjacent healthy tissues. Compared with healthy controls, plasma levels of HAND2-AS1 were lower, while levels of transforming growth factor β (TGF-β) were higher in NSCLC patients. A significant negative correlation between plasma levels of HAND2-AS1 and TGF-β1 was found in NSCLC patients but not in healthy controls. LncRNA HAND2-AS1 overexpression inhibits, while exogenous TGF-β1 treatment promotes cell migration and invasion ability and cancer cell stemness. Cancer cells with lncRNA HAND2-AS1 overexpression showed down-regulated TGF-β1, while TGF-β1 treatment showed no significant effects on lncRNA HAND2-AS1 expression. TGF-β1 attenuated the inhibitory effects of lncRNA HAND2-AS1 overexpression on cell migration, invasion and stemness. We concluded that lncRNA HAND2-AS1 may regulate the migration, invasion and stemness of NSCLC cells through interactions with TGF-β1.
Ohno Y, Shingyoku S, Miyake S, et al.Differential regulation of the sphere formation and maintenance of cancer-initiating cells of malignant mesothelioma via CD44 and ALK4 signaling pathways.
Oncogene. 2018; 37(49):6357-6367 [PubMed
] Free Access to Full Article Related Publications
Malignant mesothelioma (MM) has a poor prognosis and is largely resistant to standard treatments, so it is important to seek novel therapeutic strategies for this disease. Cancer-initiating cells (CICs) were previously identified in MM using stem cell-associated markers in combination with spheroid cultures. However, the mechanisms underlying the induction and maintenance of CICs in MM remain to be fully explored. Here we showed that the CICs, which had high aldehyde dehydrogenase levels (ALDH
Tammi MI, Oikari S, Pasonen-Seppänen S, et al.Activated hyaluronan metabolism in the tumor matrix - Causes and consequences.
Matrix Biol. 2019; 78-79:147-164 [PubMed
] Related Publications
Hyaluronan accumulates in the stroma of several solid tumors and promotes their progression. Both enhanced synthesis and fragmentation of hyaluronan are required as a part of this inflammatory process resembling wound healing. Increased expression of the genes of hyaluronan synthases (HAS1-3) are infrequent in human tumors, while posttranslational modifications that activate the HAS enzymes, and glucose shunted to the UDP-sugar substrates HASs, can have crucial contributions to tumor hyaluronan synthesis. The pericellular hyaluronan influences virtually all cell-cell and cell-matrix interactions, controlling migration, proliferation, apoptosis, epithelial to mesenchymal transition, and stem cell functions. The catabolism by hyaluronidases and free radicals appears to be as important as synthesis for the inflammation that promotes tumor growth, since the receptors mediating the signals create specific responses to hyaluronan fragments. Targeting hyaluronan metabolism shows therapeutic efficiency in animal experiments and early clinical trials.
MicroRNA‑29a (miR‑29a) has recently been in the spotlight as a tumor suppressor whose encoding gene is frequently suppressed in cancers. The aim of the present study was to investigate the biological functions and underlying molecular mechanism by which miR‑29a‑3p suppresses gastric cancer peritoneum metastasis. Cell proliferation, colony‑forming, wound healing and Transwell migration assays were performed in the present study. MiR‑29a‑3p expression was markedly decreased in gastric cancer cell lines with stronger metastatic potential. Silencing miR‑29a‑3p expression promoted gastric cancer cell proliferation, colony‑forming, migration and invasion. By contrast, overexpression of miR‑29a‑3p inhibited these biological phenotypes. In addition, it was revealed that miR‑29a‑3p functioned through downregulating hyaluronan synthase 3 expression. Collectively, dysregulated miR‑29a‑3p expression in gastric cancer cells was associated with malignant properties primarily relevant to migration and metastasis. The results suggest that miR‑29a‑3p may be a potential therapeutic target for gastric cancer.
Karalis TT, Heldin P, Vynios DH, et al.Tumor-suppressive functions of 4-MU on breast cancer cells of different ER status: Regulation of hyaluronan/HAS2/CD44 and specific matrix effectors.
Matrix Biol. 2019; 78-79:118-138 [PubMed
] Related Publications
The malignant phenotype of various cancers is linked to enhanced expression of hyaluronan, a pro-angiogenic glycosaminoglycan whose expression is suppressed by 4-methylumbelliferone (4-MU), a non-toxic oral agent used as a dietary supplement to improve health and combat prostate cancer. In this study, we investigated the role of 4-MU in mammary carcinoma cells with distinct malignant phenotypes and estrogen receptor (ER) status, a major prognostic factor in the clinical management of breast cancers. We focused on two breast cancer cell lines, the low metastatic and ERα+ MCF-7 cells, and the highly-aggressive and ERα- MDA-MB-231 cells. Treatment with 4-MU caused a dose-dependent decrease of hyaluronan accumulation in the extracellular matrix as well as within the breast cancer cells, most prevalent in cells lacking ERα. This decrease in hyaluronan was accompanied by suppression of Hyaluronan Synthase 2 (HAS2), the major enzyme responsible for the synthesis of hyaluronan, and by induction of hyaluronidases (HYALs) -1 and -2. Moreover, 4-MU induced intense phenotypic changes and substantial loss of CD44, a major hyaluronan receptor, from cell protrusions. Importantly, 4-MU evoked differential effects depending on the absence or presence of ERα. Only the ERα+ cells showed signs of apoptosis, as determined by cleaved PARP-1, and anoikis as shown by concurrent loss of E-cadherin and β-catenin. Interestingly, 4-MU significantly reduced migration, adhesion and invasion of ERα- breast cancer cells, and concurrently reduced the expression and activity of several matrix degrading enzymes and pro-inflammatory molecules with tumor-promoting functions. Collectively, our findings suggest that 4-MU could represent a novel therapeutic for specific breast cancer subtypes with regard to their ER status via suppression of hyaluronan synthesis and regulation of HAS2, CD44, matrix-degrading enzymes and inflammatory mediators.
Yoo KC, Suh Y, An Y, et al.Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation.
Oncogene. 2018; 37(24):3317-3328 [PubMed
] Related Publications
Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.
Heldin P, Lin CY, Kolliopoulos C, et al.Regulation of hyaluronan biosynthesis and clinical impact of excessive hyaluronan production.
Matrix Biol. 2019; 78-79:100-117 [PubMed
] Related Publications
The tightly regulated biosynthesis and catabolism of the glycosaminoglycan hyaluronan, as well as its role in organizing tissues and cell signaling, is crucial for the homeostasis of tissues. Overexpression of hyaluronan plays pivotal roles in inflammation and cancer, and markedly high serum and tissue levels of hyaluronan are noted under such pathological conditions. This review focuses on the complexity of the regulation at transcriptional and posttranslational level of hyaluronan synthetic enzymes, and the outcome of their aberrant expression and accumulation of hyaluronan in clinical conditions, such as systemic B-cell cancers, aggressive breast carcinomas, metabolic diseases and virus infection.
Oikari S, Kettunen T, Tiainen S, et al.UDP-sugar accumulation drives hyaluronan synthesis in breast cancer.
Matrix Biol. 2018; 67:63-74 [PubMed
] Related Publications
Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor. The content of UDP-GlcUA was 4 times, and that of UDP-GlcNAc 12 times higher in the tumors as compared to normal glandular tissue obtained from breast reductions. The surge of UDP-GlcNAc correlated with an elevated mRNA expression of glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), one of the key enzymes in the biosynthesis of UDP-GlcNAc, and the expression of GFAT1 was also elevated. The contents of both UDP-sugars strongly correlated with tumor hyaluronan levels. Interestingly, hyaluronan content did not correlate with the mRNA levels of the hyaluronan synthases (HAS1-3), thus emphasizing the role of the UDP-sugar substrates of these enzymes. The UDP-sugars showed a trend to higher levels in ductal vs. lobular cancer subtypes. The results reveal for the first time a dramatic increase of UDP-sugars in breast cancer, and suggest that their high supply drives the accumulation of hyaluronan, a known promoter of breast cancer and other malignancies. In general, the study shows how the disturbed glucose metabolism typical for malignant tumors can influence cancer microenvironment through UDP-sugars and hyaluronan.
BACKGROUND: Breast cancer brain metastases (BCBM) develop in about 20-30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques.
METHODS: We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM.
RESULTS: The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3, BNIP3, BNIP3P1, BRIP1, CASP14, CDC25A, DMBT1, IDH2, E2F1, MYCN, RAD51, RAD54L, and VDR. A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1, SNORA2A, SNORA9, SNORA10, SNORA22, SNORA24, SNORA30, SNORA37, SNORA38, SNORA52, SNORA71A, SNORA71B, SNORA71C, SNORD13P2, SNORD15A, SNORD34, SNORD35A, SNORD41, SNORD53, and SCARNA22. The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53, BRCA1, BRCA2, ERBB2, IDH1, and IDH2. WES detected numerous mutations, some of which affecting BC associated genes as CDH1, HEPACAM, and LOXHD1.
CONCLUSIONS: Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that ∆Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, ∆Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ∆Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a ∆Np63-dependent pathway functionally important to the regulation of HNSCC progression.
Nguyen N, Kumar A, Chacko S, et al.Human hyaluronic acid synthase-1 promotes malignant transformation via epithelial-to-mesenchymal transition, micronucleation and centrosome abnormalities.
Cell Commun Signal. 2017; 15(1):48 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Human hyaluronic acid (HA) molecules are synthesized by three membrane spanning Hyaluronic Acid Synthases (HAS1, HAS2 and HAS3). Of the three, HAS1 is found to be localized more into the cytoplasmic space where it synthesizes intracellular HA. HA is a ubiquitous glycosaminoglycan, mainly present in the extracellular matrix (ECM) and on the cell surface, but are also detected intracellularly. Accumulation of HA in cancer cells, the cancer-surrounding stroma, and ECM is generally considered an independent prognostic factors for patients. Higher HA production also correlates with higher tumor grade and more genetic heterogeneity in multiple cancer types which is known to contribute to drug resistance and results in treatment failure. Tumor heterogeneity and intra-tumor clonal diversity are major challenges for diagnosis and treatment. Identification of the driver pathway(s) that initiate genomic instability, tumor heterogeneity and subsequent phenotypic/clinical manifestations, are fundamental for the diagnosis and treatment of cancer. Thus far, no evidence was shown to correlate intracellular HA status (produced by HAS1) and the generation of genetic diversity in tumors.
METHODS: We tested different cell lines engineered to induce HAS1 expression. We measured the epithelial traits, centrosomal abnormalities, micronucleation and polynucleation of those HAS1-expressing cells. We performed real-time PCR, 3D cell culture assay, confocal microscopy, immunoblots and HA-capture methods.
RESULTS: Our results demonstrate that overexpression of HAS1 induces loss of epithelial traits, increases centrosomal abnormalities, micronucleation and polynucleation, which together indicate manifestation of malignant transformation, intratumoral genetic heterogeneity, and possibly create suitable niche for cancer stem cells generation.
CONCLUSIONS: The intracellular HA produced by HAS1 can aggravate genomic instability and intratumor heterogeneity, pointing to a fundamental role of intracellular HA in cancer initiation and progression.
Nishio K, Ozawa Y, Ito H, et al.Functional expression of BMP7 receptors in oral epithelial cells. Interleukin-17F production in response to BMP7.
J Recept Signal Transduct Res. 2017; 37(5):515-521 [PubMed
] Related Publications
BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily. Recently, BMP7 has been demonstrated to be produced by salivary glands and contribute to embryonic branching in mice. The BMP7 in saliva is thought to be delivered to the oral cavity and is expected to contact with stratified squamous epithelial cells which line the surface of oral mucosa. In this study, we attempted to investigate the effects of BMP7 on oral epithelial cells.
METHODS: The expression of BMP receptors was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). OSCCs were stimulated with human recombinant BMP7 (hrBMP7) and the phosphorylation status of Smad1/5/8 was examined by western blotting. For microarray analysis, Ca9-22 cells were stimulated with 100 ng/mL of hrBMP7 and total RNA was extracted and subjected to real-time PCR. The 5'-untranslated region (5'-UTR) of IL-17 F gene was cloned to pGL4-basic vector and used for luciferase assay. Ca9-22 cells were pre-incubated with DM3189, a specific inhibitor of Smad1/5/8, for inhibition assay.
RESULTS: All isoforms of type I and type II BMP receptors were expressed in both Ca9-22 and HSC3 cells and BMP7 stimulation resulted in the phosphorylation of Smad1/5/8 in both cell lines. The microarray analysis revealed the induction of interleukin-17 F (IL-17 F), netrin G2 (NTNG2) and hyaluronan synthase 1 (HAS1). Luciferase assay using the 5'-UTR of the IL-17 F gene revealed transcriptional regulation. Induced IL-17 F production was further confirmed at the protein level by ELISA. Smad1/5/8 inhibitor pretreatment decreased IL-17 F expression levels in the cells.
Wang G, Zhao W, Gao X, et al.HNF1A‑AS1 promotes growth and metastasis of esophageal squamous cell carcinoma by sponging miR‑214 to upregulate the expression of SOX-4.
Int J Oncol. 2017; 51(2):657-667 [PubMed
] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world, marked by dysphagia and weight loss, bringing great suffering to patients. HNF1A‑AS1 (HAS1), a long non-coding RNA (lncRNA), has been identified prevalently involved in various human cancers. However, the exact effects and molecular mechanisms of HAS1 in ESCC progression are still elusive. In this study, upregulated expression of HAS1 was detected in ESCC tissues and four human ESCC cell lines (KYSE70, KYSE450, EC109 and EC970) compared with normal tissues and cell lines. Small interfering RNA (siRNA)-mediated knockdown of HAS1 largely suppressed cell proliferation and promoted cell apoptosis in KYSE70 and EC109 cells. The decreased expression of proliferation marker proteins and elevated level of apoptosis marker proteins further verified that HAS1‑siRNA suppressed cell viability in ESCC cells. Besides, the silence of HAS1 strongly reduced the wound closing rate and the number of invasive cells compared with control group. HAS1-siRNA also restrained the expression of migration marker proteins matrix metalloproteinase-9 (MMP-9) and vascular endothelial cell growth factor (VEGF). In addition, miR‑214 was predicted as a direct target of HAS1 by bioinformatics analysis. Downregulated expression of miR‑214 was elevated in KYSE70 and EC109 cells transfected with HAS1-siRNA. Subsequently, elevated expression of miR‑214 was suppressed by co-transfecting with miR‑214 inhibitor in EC109 cells pretreated with HAS1-siRNA. The result of luciferase activity assay showed that luciferase activity was strongly weakened by the combination of LncR-HAS1 WT and miR‑214 mimic. Moreover, the expression of SOX-4, a predicted target gene of miR‑214, was suppressed by HAS1-siRNA and was increased by miR‑214 inhibitor. HAS1-siRNA counteracted the effect of miR‑214 inhibitor on cell viability and mobility in EC109 cells. Finally, the in vivo experiment revealed that HAS1-siRNA abated the role of miR‑214 inhibitor in promoting tumor growth and metastasis. miR-214 also mediated the effect of HAS1 on upregulating the expression of SOX-4 in vivo. Taken together, our study indicated a HAS1-miR‑214-SOX-4 pathway in regulating the growth and metastasis of ESCC, providing a promising target for ESCC therapy.
Park GB, Ko HS, Kim DSorafenib controls the epithelial‑mesenchymal transition of ovarian cancer cells via EGF and the CD44‑HA signaling pathway in a cell type‑dependent manner.
Mol Med Rep. 2017; 16(2):1826-1836 [PubMed
] Free Access to Full Article Related Publications
Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)‑binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial‑mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription‑polymerase chain reaction. In addition, the association between EGF and CD44/HA signaling pathways in the control of mesenchymal phenotype was determined by gene silencing with small interfering RNA transfection. EGF stimulation of ovarian cancer cells increased cellular migration, mesenchymal transition, CD44 expression and the activation of matrix metalloproteinase (MMP)‑2 and MMP‑9. Sorafenib effectively suppressed the loss of epithelial characteristics in EGF‑treated SK‑OV‑3 ovarian cancer cells, via targeting the mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) pathway. Although treatment of Caov‑3 ovarian cancer cells with sorafenib blocked the expression of mesenchymal phenotypes following EGF stimulation, EGF‑activated Caov‑3 cells exhibited reduced MAPK/ERK signaling. Furthermore, EGF‑activated Caov‑3 cells increased the expression of hyaluronan synthase 2 and HA‑CD44 ligation in EGF‑exposed Caov‑3 cells, which resulted in the activation of the Ras/Raf/MEK signaling pathway, amplification of migratory activity and the expression of mesenchymal markers, including N‑cadherin and vimentin. Furthermore, silencing EGFR in SK‑OV‑3 cells and CD44 in Caov‑3 cells suppressed their migratory activity, through inhibition of the MAPK/ERK pathway. The present results suggested that EGF‑mediated signaling may regulate metastasis and invasion of ovarian cancer cells, in a cancer cell type‑dependent manner.
Zhu G, Wang S, Chen J, et al.Long noncoding RNA HAS2-AS1 mediates hypoxia-induced invasiveness of oral squamous cell carcinoma.
Mol Carcinog. 2017; 56(10):2210-2222 [PubMed
] Related Publications
A hypoxic microenvironment plays important roles in the progression of solid tumors, including oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) have gained much attention in the past few years. However, it is not clear whether lncRNAs can regulate hypoxia adaptation of OSCC or which lncRNAs participate in this process. Using a lncRNA microarray, we analyzed the aberrant lncRNA expression profiles in OSCC tissues compared with paired normal oral mucosa and in hypoxic OSCC cells compared with normoxic OSCC cells. The top 10 lncRNAs that had more than threefold increase with P-value <0.01 in both microarray data were validated by qRT-PCR. Among the top 10 lncRNAs, hyaluronan synthase 2 antisense 1 (HAS2-AS1) was the only one that has a hypoxia-responsive element (HRE) on its promoter region and has been validated to increase in OSCC tissues and in cells cultured under hypoxia. Tumor HAS2-AS1 levels were closely associated with lymph node metastasis and hypoxic tumor status in patients with OSCC. Moreover, the hypoxia-induced HAS2-AS1 expression is dependent on HIF-1α which directly binds to and activates the transcription of HAS2-AS1. In addition, HAS2-AS1 mediates hypoxia-induced epithelial mesenchymal transition of OSCC cells via stabilizing HAS2. In conclusion, our results suggest that hypoxia would induce an overexpression of HAS2-AS1 in an HIF-1α dependent manner. The increase of HAS2-AS1 plays important roles mediating the hypoxia-regulated EMT and invasiveness of OSCC.
Higher levels of hyaluronan (HA) and its receptors CD44 and RHAMM have been associated with poor prognosis and metastasis in NSCLC. In the current study, our goal was to define, using cellular and orthotopic lung tumor models, the role of HA-CD44/RHAMM signaling in lung carcinogenesis and to assess the potential of triptolide to block HA-CD44/RHAMM signaling and thereby suppress the development and progression of lung cancer. Triptolide reduced the viability of five non-small cell lung cancer (NSCLC) cells, the proliferation and self-renewal of pulmospheres, and levels of HA synthase 2 (HAS2), HAS3, HA, CD44, RHAMM, EGFR, Akt and ERK, but increased the cleavage of caspase 3 and PARP. Silencing of HAS2, CD44 or RHAMM induced similar effects. Addition of excess HA to the culture media completely abrogated the effects of triptolide and siRNAs targeting HAS2, CD44, or RHAMM. In an orthotopic lung cancer model in nude rats, intranasal administration of liposomal triptolide (400 μg/kg) for 8 weeks significantly reduced lung tumor growth as determined by bioluminescence imaging, lung weight measurements and gross and histopathological analysis of tumor burden. Also, triptolide suppressed expressions of Ki-67, a marker for cell proliferation, HAS2, HAS3, HA, CD44, and RHAMM in lung tumors. Overall, our results provide a strong rationale for mitigating lung cancer by targeting the HA-CD44/RHAMM signaling axis.
Witzel I, Marx AK, Müller V, et al.Role of HYAL1 expression in primary breast cancer in the formation of brain metastases.
Breast Cancer Res Treat. 2017; 162(3):427-438 [PubMed
] Related Publications
BACKGROUND: The incidence of brain metastases in breast cancer patients has increased in the last years. However, the knowledge about tumor cell invasion in the brain is still very limited. Based on our recent study on cDNA microarray data of breast cancer patients, we hypothesized that two enzymes involved in the hyaluronan metabolism, namely, hyaluronan synthase 2 (HAS2) and hyaluronidase 1 (HYAL1) are associated with brain metastases formation.
METHODS: Protein expression levels of hyaluronan, HAS2, and HYAL1 were analyzed in primary breast cancer, and metastatic tissue samples from different localizations (brain, bone, skin, liver, and lung) were included in four different cohorts by immunohistochemistry. Correlations of expression levels with clinical and pathological parameters were performed within the individual cohorts.
RESULTS: Higher HYAL1 expression was detected among primary tumors from patients with subsequent brain metastases compared with those without brain metastases (p = 0.011). Interestingly, brain metastatic tissue showed a significantly reduced HYAL1 expression compared with the corresponding primary tumor (p = 0.003). HYAL1 expression in brain metastases was also significantly lower than in skin, liver, and lung metastases. Further, hyaluronan staining in brain metastases was mainly located on the surface of the tumor cells, whereas in all other metastatic sites hyaluronan was only detected in the extracellular matrix. We could not show an association of HAS2 with the formation of brain metastases.
CONCLUSIONS: In conclusion, our results suggest that the enzyme HYAL1 plays a role in tumor dissemination and brain-specific colonization, rather than in subsequent metastatic out-growth.
Vanneste M, Hanoux V, Bouakka M, Bonnamy PJHyaluronate synthase-2 overexpression alters estrogen dependence and induces histone deacetylase inhibitor-like effects on ER-driven genes in MCF7 breast tumor cells.
Mol Cell Endocrinol. 2017; 444:48-58 [PubMed
] Related Publications
In breast carcinoma cells, high levels of hyaluronan (HA) and its CD44 receptor are frequently associated with alteration in estrogen signaling. We demonstrate that stable hyaluronate synthase 2 (HAS2) overexpression in estrogen receptor α (ERα) -positive MCF7 cells oppositely altered estrogen dependence of cell growth and its sensitivity towards antiestrogens. Albeit without effect on ERα expression and estradiol binding properties, HAS2 overexpression increased ERα Ser118 phosphorylation as well as transcriptional activity of estrogen in an ERE-luciferase reporter gene assay. However, HAS2 overexpression induced partial silencing of E2 driven-genes without affecting the magnitude of regulation by estradiol. This effect was associated with half-reduction in the activity of nuclear histone deacetylases (HDACs) through a post-translational mechanism likely consecutive to the enhanced expression of the histone acetyl-transferase EP300. In conclusion, increase in HA/CD44 interactions may contribute, through an HDAC inhibitor-like and ER-independent mechanism, to the silencing of estrogen-driven genes in breast carcinoma.
Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer.
Cancer metastasis is the main reason for poor patient survival. Tumor cells delaminate from the primary tumor by induction of epithelial-mesenchymal transition (EMT). EMT is mediated by key transcription factors, including ZEB1, activated by tumor cell interactions with stromal cells and the extracellular matrix (ECM). ZEB1-mediated EMT and motility is accompanied by substantial cell reprogramming and the acquisition of a stemness phenotype. However, understanding of the underlying mechanism is still incomplete. We identified hyaluronic acid (HA), one major ECM proteoglycan and enriched in mammary tumors, to support EMT and enhance ZEB1 expression in cooperation with CD44s. In breast cancer cell lines HA is synthesized mainly by HAS2, which was already shown to be implicated in cancer progression. ZEB1 and HAS2 expression strongly correlates in various cancer entities and high HAS2 levels associate with an early relapse. We identified HAS2, tumor cell-derived HA and ZEB1 to form a positive feedback loop as ZEB1, elevated by HA, directly activates HAS2 expression. In an in vitro differentiation model HA-conditioned medium of breast cancer cells is enhancing osteoclast formation, an indicator of tumor cell-induced osteolysis that facilitates formation of bone metastasis. In combination with the previously identified ZEB1/ESRP1/CD44s feedback loop, we found a novel autocrine mechanism how ZEB1 is accelerating EMT.
Zhang HY, Liang F, Wang F, et al.In Vitro Effects of HAS-2 Gene Silencing on the Proliferation and Apoptosis of the MCF-7 Human Breast Cancer Cell Line.
Cell Physiol Biochem. 2016; 40(3-4):807-817 [PubMed
] Related Publications
BACKGROUND: Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. This study is aimed to investigate the effects of silencing the HAS-2 gene on the proliferation and apoptosis of human breast cancer cells.
METHODS: MCF-7 cells were collected and assigned into control, scrambled siRNA and HAS-2- siRNA groups. After transfection, the morphological changes in the MCF-7 cells were observed using phase contrast microscopy. qRT-PCR and Western blot assays were used to detect the mRNA and protein expression of apoptosis-related proteins. CCK-8 and flow cytometry were performed to evaluate cell proliferation, the cell cycle and apoptosis.
RESULTS: In the control and the scrambled siRNA groups, cells grew adhered to the wall and mainly showed a spindle shape with a clear nucleolus. Compared with the control and scrambled siRNA groups, increases in the number of cells in early apoptosis and metaphase cells in apoptosis were observed in the HAS-2-siRNA group. The HAS-2-siRNA group showed decreased expression of HAS-2 relative to that in the control and scrambled siRNA groups. No significant differences in cell proliferation, cell cycle distribution or apoptosis were noted between the control and scrambled siRNA groups. In the HAS-2-siRNA group, the cell proliferation ability decreased significantly, but the number of cells in the G0/G1 stage, the number of apoptotic cells and the expression of caspase-3 and caspase-9 increased significantly.
CONCLUSION: Our findings indicate that HAS-2 gene silencing may inhibit proliferation and promote apoptosis in the MCF-7 human breast cancer cell line.
BACKGROUND: Hyaluronan synthases (HAS) control the biosynthesis of hyaluronan (HA) and critically modulate the tumor microenviroment. Cancer-associated fibroblasts (CAFs) affect the progression of a tumor by remolding the matrix. However, little is known about the role of HAS from CAFs in this process. This study aimed to determine the role of hyaluronan synthase 2 (HAS2) from CAFs in the progression of oral squamous cell carcinoma (OSCC) invasion.
METHODS: HAS isoforms 1, 2, and 3 in paired sets of CAFs and normal fibroblasts (NFs) were examined by real-time PCR, and the expression of HAS2 and α-SMA in OSCC tissue sections was further evaluated using immunohistochemical staining. Furthermore, we used a conditioned culture medium model to evaluate the effects of HAS2 from CAFs on the invasion and epithelial-mesenchymal transition (EMT) of the oral cancer cells Cal27. Finally, we compared the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between CAFs and NF, and between CAFs with or without HAS2 knockdown using an antibody array and western blotting.
RESULTS: CAFs expressed higher levels of HAS2 than the paired NFs. HAS2 expression was consistent with α-SMA-positive myofibroblasts in the stroma of OSCC, and these were significantly correlated advanced clinical stages and cervical lymph node metastasis. Knocking down HAS2 with a specific siRNA or treatment with a HAS inhibitor markedly attenuated CAF-induced invasion and EMT of Cal27 cells. Higher MMP1 and lower TIMP1 levels were detected in the supernatants of CAFs relative to NFs. Knocking down HAS2 could decrease the expression of MMP1 and increase that of TIMP1 in CAFs.
CONCLUSIONS: HAS2 is one of the key regulators responsible for CAF-mediated OSCC progression and acts by modulating the balance of MMP1 and TIMP1.
Nagase H, Kudo D, Suto A, et al.4-Methylumbelliferone Suppresses Hyaluronan Synthesis and Tumor Progression in SCID Mice Intra-abdominally Inoculated With Pancreatic Cancer Cells.
Pancreas. 2017; 46(2):190-197 [PubMed
] Free Access to Full Article Related Publications
OBJECTIVES: Pancreatic ductal adenocarcinoma contains large amounts of the glycosaminoglycan hyaluronan (HA), which is involved in various physiological processes. Here, we aimed to clarify the anticancer mechanisms of 4-methylumbelliferone (MU), a well-known HA synthesis inhibitor.
METHODS: MIA PaCa-2 human pancreatic cancer cells were used. We evaluated cellular proliferation, migration, and invasion in the presence of MU, exogenous HA, and an anti-CD44 antibody. We also analyzed apoptosis, CD44 expression, and HA-binding ability using flow cytometry. The HA content in tumor tissue was quantified and histopathologically investigated in mice who had been inoculated with cancer cells.
RESULTS: In vitro, MU inhibited pericellular HA matrix formation; however, HAS3 mRNA was up-regulated. Treatment with 0.5 mM MU suppressed cellular proliferation by 26.4%, migration by 14.7%, and invasion by 22.7%. Moreover, MU also significantly increased apoptosis. CD44 expression and HA-binding ability were not altered by MU. In vivo, MU suppressed HA accumulation in pancreatic tumors and improved survival times in tumor-bearing mice.
CONCLUSIONS: 4-Methylumbelliferone indirectly caused apoptosis in pancreatic cancer cells by inhibiting HA production. 4-Methylumbelliferone may be a promising agent in the treatment of pancreatic cancer.
A number of long non-coding RNAs (lncRNAs) have been found to play critical roles in oncogenesis and tumor progression. We aimed to investigate whether lncRNAs could act as prognostic biomarkers for papillary thyroid cancer (PTC) that may assist us in evaluating disease status and prognosis for patients. We found 220 lncRNAs with expression alteration from the annotated 2773 lncRNAs approved by the HUGO gene nomenclature committee in The Cancer Genome Atlas (TCGA) dataset, of which FAM41C, CTBP1-AS2, LINC00271, HAR1A, LINC00310 and HAS2-AS1 were associated with recurrence. After adjusting classical clinicopathogical factors and BRAF
Karousou E, Misra S, Ghatak S, et al.Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer.
Matrix Biol. 2017; 59:3-22 [PubMed
] Related Publications
Synthesis, deposition, and interactions of hyaluronan (HA) with its cellular receptor CD44 are crucial events that regulate the onset and progression of tumors. The intracellular signaling pathways initiated by HA interactions with CD44 leading to tumorigenic responses are complex. Moreover, HA molecules may perform dual functions depending on their concentration and size. Overexpression of variant isoforms of CD44 (CD44v) is most commonly linked to cancer progression, whereas their loss is associated with inhibition of tumor growth. In this review, we highlight that the regulation of HA synthases (HASes) by post-translational modifications, such as O-GlcNAcylation and ubiquitination, environmental factors and the action of microRNAs is important for HA synthesis and secretion in the tumor microenvironment. Moreover, we focus on the roles and interactions of CD44 with various proteins that reside extra- and intracellularly, as well as on cellular membranes with particular reference to the CD44-HA axis in cancer stem cell functions, and the importance of CD44/CD44v6 targeting to inhibit tumorigenesis.
BACKGROUND: With the advent of large scale biological data collection for various diseases, data analysis pipelines and workflows need to be established to build frameworks for integrative analysis. Here the authors present a pipeline for identifying disease specific gene-drug interactions using CNV (Copy Number Variation) and clinical data from the TCGA (The Cancer Genome Atlas) project. Two cancer types were selected for analysis, LGG (Brain lower grade glioma) and GBM (Glioblastoma multiforme), due to the possible progression from LGG to GBM in some cases. The copy number and clinical data were then used to preform survival analysis on a gene by gene basis on sub-populations of patients exposed to a given drug.
RESULTS: Several gene-drug interactions are identified, where the copy number of a gene is associated to survival of a patient exposed to a certain drug. Both Irinotecan/HAS2 (Hyaluronan synthase 2) and Bevacizumab/PGAM1 (Phosphoglycerate mutase 1) are interactions found in this study with independent confirmation. Independent work in colon, breast cancer and leukemia (Györffy, Breast Cancer Res Treat 123:725-731, 2010; Mueller, Mol Cancer Ther 11:3024-3032, 2010; Hitosugi, Cancer Cell 13:585-600, 2012) showed these two interactions can lead to increased survival.
CONCLUSION: While the pipeline produced several possible interactions where increased survival is linked to normal or increased copy number of a given gene for patients treated with a given drug, no instance of low copy number or full deletion was linked to increased survival. The development of this pipeline shows a promising utility to identify possible beneficial gene-drug interactions that could improve patient survival and may illustrate some of the problems inherent in this kind of analysis on these data.
Uchakina ON, Ban H, Hostetler BJ, McKallip RJInhibition of hyaluronic acid formation sensitizes chronic myelogenous leukemia to treatment with doxorubicin.
Glycobiology. 2016; 26(11):1171-1179 [PubMed
] Related Publications
In the current study we examined the ability of 4-methylumbelliferone (4-MU), which can inhibit hyaluronic acid synthesis, to sensitize K562 chronic myelogenous leukemia (CML) cells to doxorubicin therapy. Exposure of K562 cells to doxorubicin led to increased hyaluronic acid synthase (HAS) gene expression and increased levels of cell surface hyaluronic acid. Furthermore, exposure of K562 cells to exogenous HA caused resistance to doxorubicin-induced cell death. The combination of low dose 4-MU and doxorubicin led to increased apoptosis when compared to higher doses of any agent alone. Additionally, treatment with 4-MU led to a significant reduction in doxorubicin-induced increase in HA cell surface expression. Mechanistically, 4-MU treatment led to an increase in p38 activation and PARP cleavage. The role of p38 in 4-MU/doxorubicin-treated K562 cells was confirmed when p38 inhibitors led to protection from 4-MU/doxorubicin-induced apoptosis. Together, results from this study suggest that treatment with 4-MU increases the sensitivity of CML to chemotherapeutics by decreasing their HA-mediated resistance to apoptosis.
Zhang H, Tsang JY, Ni YB, et al.Hyaluronan synthase 2 is an adverse prognostic marker in androgen receptor-negative breast cancer.
J Clin Pathol. 2016; 69(12):1055-1062 [PubMed
] Related Publications
AIMS: The important role of hyaluronan synthase 2 (HAS2), an isozyme responsible for hyaluronan synthesis, in cancer has been increasingly recognised. However, only a few studies with inconsistent results have been reported in breast cancers. With a large cohort, we aim to determine the clinical significance of HAS2 in breast cancers.
METHODS: We examined HAS2 expression in 1142 breast cancers using immunohistochemistry.
RESULTS: HAS2 was associated with both prognostically favourable (androgen receptor (AR), p<0.001) and unfavourable (basal and epithelial mesenchymal transition markers, p≤0.039) biomarkers. In addition, HAS2 showed differential associations with various features and outcome between AR+ and AR- subgroups. HAS2+AR- breast cancers showed significantly worse outcome than other subgroups, and HAS2+AR- subgroup was an independent adverse prognostic factor for disease-free survival (HR 1.309, p=0.046). Interestingly, HAS2 was associated with many poor prognostic features (including higher grade, lymphovascular invasion, basal-like breast cancer subtype, high Ki67 and basal marker expression) only in AR-, but not AR+ breast cancers.
CONCLUSIONS: HAS2 has been proposed to be a target for therapeutic intervention in cancer. Our findings suggested a possible antagonistic role of AR pathway on HAS2 function. It will be interesting to further investigate their precise interaction, which may have important implication in HAS2 targeting.