TWIST2

Gene Summary

Gene:TWIST2; twist family bHLH transcription factor 2
Aliases: AMS, FFDD3, BBRSAY, DERMO1, SETLSS, bHLHa39
Location:2q37.3
Summary:The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found. [provided by RefSeq, Apr 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:twist-related protein 2
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
Show (22)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Fibroblasts
  • CD Antigens
  • Cancer Gene Expression Regulation
  • Young Adult
  • Epithelial Cells
  • ras Proteins
  • Ovarian Cancer
  • Transcription Factors
  • Western Blotting
  • Taiwan
  • Transfection
  • Squamous Cell Carcinoma
  • snail family transcription factors
  • Adenocarcinoma
  • beta Catenin
  • Up-Regulation
  • Neoplastic Cell Transformation
  • Chromosome 2
  • Cervical Cancer
  • Cell Movement
  • Cell Differentiation
  • Zinc Finger E-box Binding Homeobox 2
  • Oral Cavity Cancer
  • Epithelial-Mesenchymal Transition
  • Cell Proliferation
  • Neoplasm Metastasis
  • Promoter Regions
  • Immunohistochemistry
  • DNA Methylation
  • Repressor Proteins
  • Cadherins
  • MicroRNAs
  • Biomarkers, Tumor
  • Apoptosis
  • Vimentin
  • Neoplasm Invasiveness
  • Nuclear Proteins
  • Down-Regulation
  • Xenograft Models
  • Transcription
  • Gene Expression Profiling
Tag cloud generated 01 September, 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: TWIST2 (cancer-related)

Demin DE, Afanasyeva MA, Uvarova AN, et al.
Constitutive Expression of NRAS with Q61R Driver Mutation Activates Processes of Epithelial-Mesenchymal Transition and Leads to Substantial Transcriptome Change of Nthy-ori 3-1 Thyroid Epithelial Cells.
Biochemistry (Mosc). 2019; 84(4):416-425 [PubMed] Related Publications
The Q61R mutation of the NRAS gene is one of the most frequent driver mutations of thyroid cancer. Tumors with this mutation are characterized by invasion into blood vessels and formation of distant metastases. To study the role of this mutation in the growth of thyroid cancer, we developed a model system on the basis of thyroid epithelial cell line Nthy-ori 3-1 transduced by a lentiviral vector containing the NRAS gene with the Q61R mutation. It was found that the expression of NRAS(Q61R) in thyroid epithelial cells has a profound influence on groups of genes involved in the formation of intercellular contacts, as well as in processes of epithelial-mesenchymal transition and cell invasion. The alteration in the expression of these genes affects the phenotype of the model cells, which acquire traits of mesenchymal cells and demonstrate increased ability for survival and growth without attachment to the substrate. The key regulators of these processes are transcription factors belonging to families SNAIL, ZEB, and TWIST, and in different types of tumors the contribution of each individual factor can vary greatly. In our model system, phenotype change correlates with an increase in the expression of SNAIL2 and TWIST2 factors, which indicates their possible role in regulating invasive growth of thyroid cancer with the mutation of NRAS(Q61R).

Zhang Q, Mao Z, Sun J
NF-κB inhibitor, BAY11-7082, suppresses M2 tumor-associated macrophage induced EMT potential via miR-30a/NF-κB/Snail signaling in bladder cancer cells.
Gene. 2019; 710:91-97 [PubMed] Related Publications
BACKGROUND: Chronic inflammatory microenvironment has been shown to play a key role in initiating tumorigenesis and facilitating malignant progression. Primary tumors surrounded with and infiltrated by tumor-associated macrophages (TAMs) significantly promote the epithelial-to-mesenchymal transition (EMT) and distant metastasis in urothelial bladder cancer.
METHODS: In this study, we aimed to explore the potential of targeting TAMs for the treatment of malignant bladder cancer.
RESULTS: First, we found a higher number of TAMs, CD68 (pan-macrophage marker), and clever-1 (M2 macrophage marker) was associated with a higher pT category and grade in a cohort of 108 patients. In vitro assays showed that the co-culture of TAMs promoted the metastatic potential in HTB-1 and T24 by up-regulating EMT markers including Snail, VEGF and Vimentin, as well as oncogenic markers such as β-catenin and NF-κB. More importantly, M2 co-cultured HTB-1 and T24 showed an increased level of metastatic microRNA, miR-30. Silencing of miR-30 resulted in the reduced metastatic potential, migration/invasion, in association with the decreased expression of Twist1 and Vimentin. The addition of BAY11-7082 into the TAM/cancer co-culture system significantly reduced the M2 phenotype and tumorigenic properties. Coincidentally, miR-30a level was significantly lowered in the presence of BAY11-7082.
CONCLUSION: Our study demonstrated that AMs promoted metastatic potential of bladder cancer cells via promoting EMT through the increase of miR-30a. BAY11-7082 treatment suppressed both oncogenic and metastatic potential in bladder cancer cells while preventing the M2 polarization of TAMs.

Matsunuma R, Chan DW, Kim BJ, et al.
DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer.
Proc Natl Acad Sci U S A. 2018; 115(51):E11978-E11987 [PubMed] Free Access to Full Article Related Publications
A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive ([Formula: see text]) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative ([Formula: see text]) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

Scott CM, Wong EM, Joo JE, et al.
Genome-wide DNA methylation assessment of 'BRCA1-like' early-onset breast cancer: Data from the Australian Breast Cancer Family Registry.
Exp Mol Pathol. 2018; 105(3):404-410 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Breast cancers arising in women carrying a germline mutation in BRCA1 are typically high-grade, early-onset and have distinct morphological features (BRCA1-like). However, the majority of early-onset breast cancers of this morphological type are not associated with germline BRCA1 mutations or constitutional BRCA1 promoter methylation. We aimed to assess DNA methylation across the genome for associations with the "BRCA1-like" morphology. Genome-wide methylation in blood-derived DNA was measured using the Infinium HumanMethylation450K BeadChip assay for women under the age of 40 years participating in the Australian Breast Cancer Family Study (ABCFS) diagnosed with: i) BRCA1-like breast cancer (n = 30); and ii) breast cancer without BRCA1-like morphological features (non BRCA1-like; n = 30), and age-matched unaffected women (controls; n = 30). Corresponding tumour-derived DNA from 43 of the affected women was also assessed. Methylation of blood-derived DNA was found to be elevated across 17 consecutive marks in the BRCA1 promoter region and decreased at several other genomic regions (including TWIST2 and CTBP1) for 7 women (23%) diagnosed with BRCA1-like breast cancer compared with women in the other groups. Corresponding tumour-derived DNA available from 5 of these 7 women had elevated methylation within the BRCA1 and SPHK2 promoter region and decreased methylation within the ADAP1, IGF2BP3 and SPATA13 promoter region when compared with the other breast tumours. These methylation marks could be biomarkers of risk for BRCA1-like breast cancer, and could be responsible in part for their distinctive morphological features and biology. As such, they may assist with prevention and targeted therapies for this cancer subtype.

Maekawa T, Fukaya R, Takamatsu S, et al.
Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer.
Biochem Biophys Res Commun. 2018; 506(4):962-969 [PubMed] Related Publications
(Aim) Bacterial infection underlies the pathogenesis of many human diseases, including acute and chronic inflammation. Here, we investigated a possible role for bacterial infection in the progression of chronic pancreatitis. (Materials and Methods) Pancreatic juice was obtained from patients with pancreatic cancer (n = 20) or duodenal cancer/bile duct cancer (n = 16) and subjected to PCR using universal primers for the bacterial 16S ribosomal RNA gene. Bacterial species were identified by PCR using bile samples from four pancreatic cancer patients. PCR products were subcloned into T-vectors, and the sequences were then analyzed. Immunohistochemical and serologic analyses for Enterococcus faecalis infection were performed on a large cohort of healthy volunteers and patients with chronic pancreatitis or pancreatic cancer and on mice with caerulein-induced chronic pancreatitis. The effect of E. faecalis antigens on cytokine secretion by pancreatic cancer cells was also investigated. (Results) We found that 29 of 36 pancreatic juice samples were positive for bacterial DNA. Enterococcus and Enterobacter species were detected primarily in bile, which is thought to be a pathway for bacterial infection of the pancreas. Enterococcus faecalis was also detected in pancreatic tissue from chronic pancreatitis and pancreatic cancer patients; antibodies to E. faecalis capsular polysaccharide were elevated in serum from chronic pancreatitis patients. Enterococcus-specific antibodies and pancreatic tissue-associated E. faecalis were detected in mice with caerulein-induced chronic pancreatitis. Addition of Enterococcus lipoteichoic acid and heat-killed bacteria induced expression of pro-fibrotic cytokines by pancreatic cancer cells in vitro. (Conclusion) Infection with E. faecalis may be involved in chronic pancreatitis progression, ultimately leading to development of pancreatic cancer.

Kusonmano K, Halle MK, Wik E, et al.
Identification of highly connected and differentially expressed gene subnetworks in metastasizing endometrial cancer.
PLoS One. 2018; 13(11):e0206665 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
We have identified nine highly connected and differentially expressed gene subnetworks between aggressive primary tumors and metastatic lesions in endometrial carcinomas. We implemented a novel pipeline combining gene set and network approaches, which here allows integration of protein-protein interactions and gene expression data. The resulting subnetworks are significantly associated with disease progression across tumor stages from complex atypical hyperplasia, primary tumors to metastatic lesions. The nine subnetworks include genes related to metastasizing features such as epithelial-mesenchymal transition (EMT), hypoxia and cell proliferation. TCF4 and TWIST2 were found as central genes in the subnetwork related to EMT. Two of the identified subnetworks display statistically significant association to patient survival, which were further supported by an independent validation in the data from The Cancer Genome Atlas data collection. The first subnetwork contains genes related to cell proliferation and cell cycle, while the second contains genes involved in hypoxia such as HIF1A and EGLN3. Our findings provide a promising context to elucidate the biological mechanisms of metastasis, suggest potential prognostic markers and further identify therapeutic targets. The pipeline R source code is freely available, including permutation tests to assess statistical significance of the identified subnetworks.

Wang S, Scharadin TM, Zimmermann M, et al.
Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel.
Chem Res Toxicol. 2018; 31(12):1293-1304 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to

Shabani N, Razaviyan J, Paryan M, et al.
Evaluation of miRNAs expression in medullary thyroid carcinoma tissue samples: miR-34a and miR-144 as promising overexpressed markers in MTC.
Hum Pathol. 2018; 79:212-221 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) is a rare neoplasia derived from neural parafollicular C cells. MicroRNAs (miRNAs) are small regulatory RNAs with essential roles in the biology of cancers such as MTC and can be applied as diagnostic markers. According to previous studies, miR-144 and miR-34 and their two oncogenes target, mammalian target of rapamycin (mTOR) and AXL receptor tyrosine kinase (AXL), were selected for further investigations in our study. Thirty MTC samples as well as thirty adjacent normal thyroid tissues were applied in this study including 28 formalin-fixed, paraffin-embedded (FFPE) and 2 fresh-frozen MTC samples. RNA extraction and complementary DNA (cDNA) synthesis were performed for all samples. After primer pairs and probes were designed, real-time polymerase chain reaction (real-time PCR) method was used, and the results were analyzed using 2

Perera-Bel J, Hutter B, Heining C, et al.
From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards.
Genome Med. 2018; 10(1):18 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
BACKGROUND: A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene-drug interactions complicates the task of assigning clinical significance to genomic variants.
METHODS: Here we present a method that automatically matches patient-specific genomic alterations to treatment options. The method relies entirely on public knowledge of somatic variants with predictive evidence on drug response. The output report is aimed at supporting clinicians in the task of finding the clinical meaning of genomic variants. We applied the method to 1) The Cancer Genome Atlas (TCGA) and Genomics Evidence Neoplasia Information Exchange (GENIE) cohorts and 2) 11 patients from the NCT MASTER trial whose treatment discussions included information on their genomic profiles.
RESULTS: Our reporting strategy showed a substantial number of patients with actionable variants in the analyses of TCGA and GENIE samples. Notably, it was able to reproduce experts' treatment suggestions in a retrospective study of 11 patients from the NCT MASTER trial. Our results establish a proof of concept for comprehensive, evidence-based reports as a supporting tool for discussing treatment options in tumor boards.
CONCLUSIONS: We believe that a standardized method to report actionable somatic variants will smooth the incorporation of NGS in the clinical context. We anticipate that tools like the one we present here will become essential in summarizing for clinicians the growing evidence in the field of precision medicine. The R code of the presented method is provided in Additional file 6 and available at https://github.com/jperera-bel/MTB-Report .

Dominguez-Valentin M, Nakken S, Tubeuf H, et al.
Identification of genetic variants for clinical management of familial colorectal tumors.
BMC Med Genet. 2018; 19(1):26 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
BACKGROUND: The genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines.
METHODS: The Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays.
RESULTS: We identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing.
CONCLUSIONS: Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.

Bowers LW, Rossi EL, McDonell SB, et al.
Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models.
Mol Cancer Res. 2018; 16(5):869-879 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). Preclinical models of TNBC were used to test the hypothesis that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, received either a control diet (10% kcal from fat) or a diet-induced obesity regimen (DIO, 60% kcal from fat) for up to 42 weeks (

Wei WF, Zhou CF, Wu XG, et al.
MicroRNA-221-3p, a TWIST2 target, promotes cervical cancer metastasis by directly targeting THBS2.
Cell Death Dis. 2017; 8(12):3220 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
MicroRNAs have implicated in the relapse and metastasis of cervical cancer, which is the leading cause of cervical cancer-related mortality. However, the underlying molecular mechanisms need further elucidation. Our present study revealed that miR-221-3p is transcriptionally promoted in metastatic cervical cancer tissues compared with non-metastatic cervical cancer tissues. Forced overexpression of miR-221-3p facilitated EMT and promoted cell migration and invasion in vitro and lymphatic metastasis in vivo. Twist homolog 2 (TWIST2) was found to be a key transcription factor binding to the promoter of miR-221-3p. Inhibitors of miR-221-3p drastically reduced the induction of EMT and decreased cell migration and invasion mediated by TWIST2. By combined computational and experimental approaches, THBS2 was recognized to be an important downstream target gene of miR-221-3p. In cervical cancer tissues, especially with lymphatic metastasis, miR-221-3p and TWIST2 were increased and THBS2 was decreased, suggesting that TWIST2 induces miR-221-3p expression and consequently suppresses its direct target THBS2 in lymphatic metastasis CC. Our findings uncover a mechanistic role for miR-221-3p in lymph node metastasis, suggesting that miR-221-3p is upregulated by the transcription factor TWIST2 and downregulates its target THBS2, which may potentially promote lymph node metastasis in cervical cancer.

Efanov AA, Brenner AV, Bogdanova TI, et al.
Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer.
J Natl Cancer Inst. 2018; 110(4):371-378 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Background: Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood.
Methods: In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided.
Results: Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features.
Conclusions: Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident.

Kou B, Liu W, Tang X, Kou Q
HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-β/Smad2 signaling pathway.
Oncol Rep. 2018; 39(1):101-108 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E‑cadherin level was upregulated, while N‑cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786‑O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-β and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-β overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-β deficiency impeded the pro‑metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-β-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.

Bernhardt S, Bayerlová M, Vetter M, et al.
Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors.
Breast Cancer Res. 2017; 19(1):112 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
BACKGROUND: Breast cancer tumors are known to be highly heterogeneous and differences in their metabolic phenotypes, especially at protein level, are less well-understood. Profiling of metabolism-related proteins harbors the potential to establish new patient stratification regimes and biomarkers promoting individualized therapy. In our study, we aimed to examine the relationship between metabolism-associated protein expression profiles and clinicopathological characteristics in a large cohort of breast cancer patients.
METHODS: Breast cancer specimens from 801 consecutive patients, diagnosed between 2009 and 2011, were investigated using reverse phase protein arrays (RPPA). Patients were treated in accordance with national guidelines in five certified German breast centers. To obtain quantitative expression data, 37 antibodies detecting proteins relevant to cancer metabolism, were applied. Hierarchical cluster analysis and individual target characterization were performed. Clustering results and individual protein expression patterns were associated with clinical data. The Kaplan-Meier method was used to estimate survival functions. Univariate and multivariate Cox regression models were applied to assess the impact of protein expression and other clinicopathological features on survival.
RESULTS: We identified three metabolic clusters of breast cancer, which do not reflect the receptor-defined subtypes, but are significantly correlated with overall survival (OS, p ≤ 0.03) and recurrence-free survival (RFS, p ≤ 0.01). Furthermore, univariate and multivariate analysis of individual protein expression profiles demonstrated the central role of serine hydroxymethyltransferase 2 (SHMT2) and amino acid transporter ASCT2 (SLC1A5) as independent prognostic factors in breast cancer patients. High SHMT2 protein expression was significantly correlated with poor OS (hazard ratio (HR) = 1.53, 95% confidence interval (CI) = 1.10-2.12, p ≤ 0.01) and RFS (HR = 1.54, 95% CI = 1.16-2.04, p ≤ 0.01). High protein expression of ASCT2 was significantly correlated with poor RFS (HR = 1.31, 95% CI = 1.01-1.71, p ≤ 0.05).
CONCLUSIONS: Our data confirm the heterogeneity of breast tumors at a functional proteomic level and dissects the relationship between metabolism-related proteins, pathological features and patient survival. These observations highlight the importance of SHMT2 and ASCT2 as valuable individual prognostic markers and potential targets for personalized breast cancer therapy.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01592825 . Registered on 3 May 2012.

Singh M, Venugopal C, Tokar T, et al.
RNAi screen identifies essential regulators of human brain metastasis-initiating cells.
Acta Neuropathol. 2017; 134(6):923-940 [PubMed] Related Publications
Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-β ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

Han M, Xu W
EMP3 is induced by TWIST1/2 and regulates epithelial-to-mesenchymal transition of gastric cancer cells.
Tumour Biol. 2017; 39(7):1010428317718404 [PubMed] Related Publications
In this study, we aimed to explore new downstream effectors of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Bioinformatic data mining was performed using data in The Cancer Genome Atlas Stomach Adenocarcinoma. Survival curves were generated using Kaplan-Meier plotter. Gastric cancer cell lines (AGS and SGC-7901) were used as in vitro cell model to investigate the regulative effect of TWIST1/2 on epithelial membrane protein 3 expression and the progression of epithelial-to-mesenchymal transition. Results showed that TWIST1 and TWIST2 are usually co-upregulated in patients with primary gastric cancer. High TWIST1 expression is associated with worse overall survival (hazard ratio = 1.26; 95% confidence interval = 1.06-1.49; p = 0.007) and also worse first progression-free survival (hazard ratio = 1.47; 95% confidence interval = 1.18-1.82; p < 0.0001). Similarly, high TWIST2 expression is associated with unfavorable overall survival (hazard ratio = 1.71; 95% confidence interval = 1.32-2.22; p < 0.0001) and progression-free survival (hazard ratio = 1.99; 95% confidence interval = 1.45-2.72; p < 0.0001). Epithelial membrane protein 3 is negatively correlated to CDH1 expression (Pearson's r = -0.46) but is positively correlated to VIM expression (Pearson's r = 0.83). Knockdown of epithelial membrane protein 3 significantly increased E-cadherin but significantly decreased Vimentin expression in AGS cells. Gastric cancer patients with metastasis have significantly higher epithelial membrane protein 3 expression than the cases without metastasis. In addition, high epithelial membrane protein 3 expression is associated with worse overall survival (hazard ratio = 2.59; 95% confidence interval = 2.06-3.26; p < 0.0001) and also worse progression-free survival (hazard ratio = 2.21; 95% confidence interval = 1.78-2.74; p < 0.0001). In conclusion, epithelial membrane protein 3 is a downstream effector of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Epithelial membrane protein 3 upregulation might be associated with gastric cancer metastasis and is a potential indicator of unfavorable overall survival and progression-free survival in gastric cancer patients.

Yang J, Zhu DM, Zhou XG, et al.
HIF-2α promotes the formation of vasculogenic mimicry in pancreatic cancer by regulating the binding of Twist1 to the VE-cadherin promoter.
Oncotarget. 2017; 8(29):47801-47815 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Vasculogenic mimicry (VM) is a blood supply modality that occurs independently of endothelial cell angiogenesis. Hypoxia and the epithelial-mesenchymal transition (EMT) induce VM formation by remodeling the extracellular matrix. Our previous study demonstrated that hypoxia-inducible factor-2 alpha (HIF-2α) promotes the progress of EMT in pancreatic cancer; however, whether HIF-2α promotes VM formation in pancreatic cancer remains unknown. In this study, we investigated HIF-2α expression and VM by immunohistochemistry in 70 pancreatic cancer patients as well as the role of Twist1and Twist2 in HIF-2α-induced VM in vitro and in vivo. We found that the overexpression of HIF-2α and VM were correlated with poor tumor differentiation, late clinical stage and lymph node metastasis, and a poor prognosis in pancreatic cancer. Moreover, the upregulation of HIF-2α in SW1990 cells induced VM formation, whereas the opposite results were found after silencing HIF-2α in AsPC-1 cells. A mechanistic study indicated that HIF-2α might regulate the binding of twist1 to vascular endothelial cadherin (VE-cadherin) to promote VM formation in pancreatic cancer cells, and that the P1 (-421bp) and P4 (-2110bp) regions of the Twist1 binding sequences are positive regulatory elements for VE-cadherin. In addition, we confirmed that the overexpression of HIF-2α increased Twist1 expression and promoted tumor growth and VM formation in pancreatic cancer xenografts in nude mice. These findings indicated that HIF-2α might play a critical role in VM and that HIF-2α and the pathway of HIF-2α inducing VM formation are potential therapeutic targets for pancreatic cancer.

Wang SS, Zimmermann M, Zhang H, et al.
A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer.
Int J Cancer. 2017; 141(3):604-613 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts-the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [

Ohta K, Naruse T, Ishida Y, et al.
TNF-α-induced IL-6 and MMP-9 expression in immortalized ameloblastoma cell line established by hTERT.
Oral Dis. 2017; 23(2):199-209 [PubMed] Related Publications
OBJECTIVE: Ameloblastoma (AM) shows locally invasive behaviour. However, biological investigations regarding regulation of gene expression associated with AM pathological features are difficult to perform, because AM cells can be passaged for a few generations due to senescence. We report a newly established immortalized AM cell line, AMB cells, by transfection with human telomerase reverse transcriptase (hTERT). Furthermore, we examined whether TNF-α modulates bone resorption-related genes, IL-6 and MMP-9 in cooperation with TGF-β or IFN-γ.
MATERIALS AND METHODS: Following transfection of an hTERT expression vector into AM cells using a non-viral method, the effects of cytokines on the expressions of IL-6 and MMP-9 mRNA were examined using real-time PCR. TNF-α-induced NF-κB activity was examined by western blotting and transcription factor assays.
RESULTS: AMB cells continued to grow for more than 100 population doublings. Stimulation with TNF-α increased IL-6 and MMP-9 mRNA expressions, as well as NF-κB activation. Furthermore, TGF-β and IFN-γ dramatically increased TNF-α-mediated expressions of MMP-9 and IL-6 mRNA, respectively, while those responses were suppressed by NF-κB inhibitor.
CONCLUSION: We established an immortalized AM cell line by hTERT transfection. TNF-α-mediated regulation of MMP-9 and IL-6 via NF-κB may play an important role in the pathological behaviour of AMs, such as bone resorption.

Wu YS, Chung I, Wong WF, et al.
Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells.
Biochim Biophys Acta Gen Subj. 2017; 1861(2):296-306 [PubMed] Related Publications
BACKGROUND: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process.
METHODS: Gene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion.
RESULTS: PSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6.
CONCLUSIONS: IL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway.
GENERAL SIGNIFICANCE: Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.

Chen HJ, Wei Z, Sun J, et al.
A recellularized human colon model identifies cancer driver genes.
Nat Biotechnol. 2016; 34(8):845-51 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.

Rojas-Puentes L, Cardona AF, Carranza H, et al.
Epithelial-mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy.
Cancer Med. 2016; 5(8):1989-99 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
We evaluated the association between epithelial-mesenchymal transition (EMT)-derived markers and expression of proteins associated with cell proliferation and tumor growth, as well as their prognostic roles, in 61 patients (mean age 52 ± 10 years) with locally advanced cervical cancer, all of whom were treated with chemoradiation and intracavitary brachytherapy. We used immunohistochemical analysis to assess the expression of proteins targeted in our investigation. Various statistical analyses were then conducted to assess protein marker associations with survival outcomes. Forty-six percent of the patients were positive for human papilloma virus. Median progression-free survival (PFS) was 6.6 months (95% confidence interval [CI]: 4.0-9.1, whereas overall survival (OS) was 30.0 months (95% CI: 11-48). Multivariate analysis demonstrated that vascular endothelial growth factor (VEGF) (P = 0.002), epidermal growth factor receptor (EGFR) (P = 0.001), and TWIST2 (P = 0.001) expression levels, as well as a tumor size <6 cm (P = 0.02), influenced OS. Changes in TWIST2 levels and loss of E-cadherin expression were correlated with VEGF and EGFR levels; furthermore, patients with high TWIST2 expression had shorter OS (P = 0.0001), as those with loss of E-cadherin (P = 0.02). OS was even shorter when positive EGFR or VEGF expression was related with EMT markers (positive EGFR + negative E-cadherin: median 14 months, 95% CI: 3-24; negative EGFR + positive E-cadherin: median 31 months, 95% CI: 14-NA; P = 0.02.). The presence of EMT markers was associated with proliferative and pro-angiogenic protein expression and influenced the prognosis of locally advanced cervical cancer.

Minas TZ, Surdez D, Javaheri T, et al.
Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model.
Oncotarget. 2017; 8(21):34141-34163 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Ewing sarcoma (ES) involves a tumor-specific chromosomal translocation that produces the EWS-FLI1 protein, which is required for the growth of ES cells both in vitro and in vivo. However, an EWS-FLI1-driven transgenic mouse model is not currently available. Here, we present data from six independent laboratories seeking an alternative approach to express EWS-FLI1 in different murine tissues. We used the Runx2, Col1a2.3, Col1a3.6, Prx1, CAG, Nse, NEFL, Dermo1, P0, Sox9 and Osterix promoters to target EWS-FLI1 or Cre expression. Additional approaches included the induction of an endogenous chromosomal translocation, in utero knock-in, and the injection of Cre-expressing adenovirus to induce EWS-FLI1 expression locally in multiple lineages. Most models resulted in embryonic lethality or developmental defects. EWS-FLI1-induced apoptosis, promoter leakiness, the lack of potential cofactors, and the difficulty of expressing EWS-FLI1 in specific sites were considered the primary reasons for the failed attempts to create a transgenic mouse model of ES.

Vellinga TT, den Uil S, Rinkes IH, et al.
Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion.
Oncogene. 2016; 35(40):5263-5271 [PubMed] Related Publications
Gene expression-based classification systems have identified an aggressive colon cancer subtype with mesenchymal features, possibly reflecting epithelial-to-mesenchymal transition (EMT) of tumor cells. However, stromal fibroblasts contribute extensively to the mesenchymal phenotype of aggressive colon tumors, challenging the notion of tumor EMT. To separately study the neoplastic and stromal compartments of colon tumors, we have generated a stroma gene filter (SGF). Comparative analysis of stroma

Yang J, Zhang X, Zhang Y, et al.
HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer.
J Exp Clin Cancer Res. 2016; 35:26 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) is a dedifferentiation process that mainly involves in mesenchymal marker upregulation, epithelial maker downregulation and cell polarity loss. Related hypoxia factors play a crucial role in EMT, however, it remains few evidence to clarify the role of HIF-2α in EMT in pancreatic cancer.
METHOD: In this study, we investigated the expression of HIF-2α and E-cadherin by immunohistochemistry in 70 pancreatic cancer patients, as well as the correlation to the clinicopathologic characteristics. Then we regulated the expression of HIF-2α in pancreatic cancer cells to examine the role of HIF-2α on invasion and migration in vitro. Finally, we tested the relation of HIF-2α and EMT related proteins by Western blot and determined whether HIF-2α regulated EMT through Twist regulating the expression of E-cadherin by Chromatin immunoprecipitation (ChIP) assay.
RESULTS: We found that HIF-2α protein was expressed positively in 67.1% (47/70) of pancreatic cancer tissues and 11.4% (8/70) of adjacent non-tumor pancreatic tissues, and there was a significant difference in the positive rate of HIF-2α protein between two groups (χ2 = 45.549, P < 0.05). In addition, the staining for HIF-2α was correlated with tumor differentiation (P < 0.05), clinical stage (P < 0.05) and lymph node metastasis (P < 0.05), while E-cadherin expression was only correlated with lymph node metastasis (P < 0.05). HIF-2α promoted cell migration, invasion in vitro, and regulated the expression of E-cadherin and MMPs, which are critical to EMT. Our further ChIP assay suggested that only Twist2 could bind to the promoter of E-cadherin in -714 bp region site, but there is no positive binding capacity in -295 bp promoter region site of E-cadherin. Clinical tissues IHC staining showed that Twist2 and E-cadherin expression had an obviously negative correlation in pancreatic cancer. Nevertheless, it had no obvious correlation between Twist1 and E-cadherin.
CONCLUSION: These findings indicated that HIF-2α promotes EMT in pancreatic cancer by regulating Twist2 binding to the promoter of E-cadherin, which meant that HIF-2α and this pathway may be effective therapeutic targets for pancreatic cancer.

Schultheis AM, Ng CK, De Filippo MR, et al.
Massively Parallel Sequencing-Based Clonality Analysis of Synchronous Endometrioid Endometrial and Ovarian Carcinomas.
J Natl Cancer Inst. 2016; 108(6):djv427 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Synchronous early-stage endometrioid endometrial carcinomas (EECs) and endometrioid ovarian carcinomas (EOCs) are associated with a favorable prognosis and have been suggested to represent independent primary tumors rather than metastatic disease. We subjected sporadic synchronous EECs/EOCs from five patients to whole-exome massively parallel sequencing, which revealed that the EEC and EOC of each case displayed strikingly similar repertoires of somatic mutations and gene copy number alterations. Despite the presence of mutations restricted to the EEC or EOC in each case, we observed that the mutational processes that shaped their respective genomes were consistent. High-depth targeted massively parallel sequencing of sporadic synchronous EECs/EOCs from 17 additional patients confirmed that these lesions are clonally related. In an additional Lynch Syndrome case, however, the EEC and EOC were found to constitute independent cancers lacking somatic mutations in common. Taken together, sporadic synchronous EECs/EOCs are clonally related and likely constitute dissemination from one site to the other.

Sakaguchi H, Muramatsu H, Okuno Y, et al.
Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia.
PLoS One. 2015; 10(12):e0145394 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
Juvenile myelomonocytic leukemia (JMML), an overlap of myelodysplastic / myeloproliferative neoplasm, is an intractable pediatric myeloid neoplasm. Epigenetic regulation of transcription, particularly by CpG methylation, plays an important role in tumor progression, mainly by repressing tumor-suppressor genes. To clarify the clinical importance of aberrant DNA methylation, we studied the hypermethylation status of 16 target genes in the genomes of 92 patients with JMML by bisulfite conversion and the pryosequencing technique. Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients. Based on the number of hypermethylated genes, patients were stratified into three cohorts based on an aberrant methylation score (AMS) of 0, 1-2, or 3-4. In the AMS 0 cohort, the 5-year overall survival (OS) and transplantation-free survival (TFS) were good (69% and 76%, respectively). In the AMS 1-2 cohort, the 5-year OS was comparable to that in the AMS 0 cohort (68%), whereas TFS was poor (6%). In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively). Epigenetic analysis provides helpful information for clinicians to select treatment strategies for patients with JMML. For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

Debruyne DN, Bhatnagar N, Sharma B, et al.
ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.
Oncogene. 2016; 35(28):3681-91 [PubMed] Article available free on PMC after 17/12/2019 Related Publications
The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.

Que L, Zhao D, Tang XF, et al.
Effects of lentivirus-mediated shRNA targeting integrin-linked kinase on oral squamous cell carcinoma in vitro and in vivo.
Oncol Rep. 2016; 35(1):89-98 [PubMed] Related Publications
Integrin-linked kinase (ILK), a highly conserved intracellular protein of serine/threonine protein kinase activities, which is associated with the integrin and growth factor receptor signaling pathway, is involved in the regulation of cell proliferation, apoptosis, differentiation, migration and epithelial-mesenchymal transition (EMT). Findings of a previous study showed that ILK overexpression was strongly correlated with a more aggressive tumor phenotype, recurrence and poor survival for oral squamous cell carcinoma (OSCC) patients, as well as some EMT markers. In order to investigate the underlying mechanisms involved, a lentivirus-mediated short hairpin RNA (shRNA) was employed to downregulate ILK. The results showed that the knockdown of ILK inhibited cell growth, adhesion and invasion ability in vitro, and OSCC cells deficient of ILK were blocked in the S phase and underwent apoptosis. Additionally, ILK shRNA inhibited EMT by impairing the expression of Snail, Slug and Twist2 and enhacning E-cadherin expression. ILK shRNA suppressed the phosphorylation of downstream signaling targets Akt and GSk-3β. In addition, the knockdown of ILK inhibited tumor growth, invasion and metastasis of xenograft tumors in vivo. These results suggested that ILK is a promising therapeutic target for the treatment of OSCC.

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