Gene Summary

Gene:CKAP4; cytoskeleton associated protein 4
Aliases: p63, CLIMP-63, ERGIC-63
Databases:HGNC, Ensembl, GeneCard, Gene
Protein:cytoskeleton-associated protein 4
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

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

Literature Analysis

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

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: CKAP4 (cancer-related)

Zhang D, Liao X, Tang Y, et al.
Warthin-like Mucoepidermoid Carcinoma of the Parotid Gland: Unusual Morphology and Diagnostic Pitfalls.
Anticancer Res. 2019; 39(6):3213-3217 [PubMed] Related Publications
BACKGROUND: Warthin-like mucoepidermoid carcinoma is a newly recognized rare entity and could be misdiagnosed as a benign Warthin tumor. We report such a case of a 36-year-old male who presented with a left parotid gland mass.
CASE REPORT: Fine-needle aspiration showed features suggestive of Warthin tumor. Following parotidectomy, grossly there was a 1.6 cm well-circumscribed multilobular mass with focal areas of cystic change. Microscopically, at low magnification it had histological features resembling Warthin tumor, while lining with squamoid cells with scattered mucocytes demonstrating mild cytologic atypia was observed at high magnification. Immunohistochemically, the tumor cells were positive for p40, p63, cytokeratin 5/6, cytokeratin 7, and cancer antigen 125, but negative for discovered on GIST-1 (DOG1). Mucicarmine stain highlighted intracellular mucin within mucocytes. Rearrangement of mastermind like transcriptional coactivator 2 (MAML2) (11q21) gene was shown to be present in tumor cells by fluorescence in situ hybridization, supporting the diagnosis of a low-grade Warthin-like mucoepidermoid carcinoma. The patient was disease-free 12 months after surgery.
CONCLUSION: Warthin-like mucoepidermoid carcinoma has not been widely recognized and can be misdiagnosed as Warthin tumor. Testing for MAML2 rearrangement provides essential support for diagnosis in difficult cases.

Gerbe A, Alame M, Dereure O, et al.
Systemic, primary cutaneous, and breast implant-associated ALK-negative anaplastic large-cell lymphomas present similar biologic features despite distinct clinical behavior.
Virchows Arch. 2019; 475(2):163-174 [PubMed] Related Publications
Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.

Lu X, Yu Y, Tan S
Long non-coding XIAP-AS1 regulates cell proliferation, invasion and cell cycle in colon cancer.
Artif Cells Nanomed Biotechnol. 2019; 47(1):767-775 [PubMed] Related Publications
Colon cancer is one of the most commonly diagnosed and deadly cancers worldwide. Further understanding of the biological mechanisms is important for exploring the molecular biomarkers and therapeutic targets of this disease. Dysregulation of long non-coding RNAs (lncRNAs) has been reported to be associated with the development and progression of various cancers. XIAP-AS1 is a novel lncRNA, which can regulate apoptosis in gastric cancer cells. However, the role of XIAP-AS1 in colorectal cancer (CRC) remains unclear. In this study, we found that XIAP-AS1 expression was significantly increased in CRC tissues and its expression showed a positive correlation with TNM stage and cumulative survival rate of CRC. To investigate whether XIAP-AS1 regulates the progression of CRC, we knocked down its expression in several CRC cell lines. CCK-8 assays showed that XIAP-AS1 knockdown remarkably suppressed CRC cell growth and arrested the cell cycle at the G0/G1 phase (flow cytometric analysis). Furthermore, XIAP-AS1 knockdown also remarkably blocked cell invasion of colon cancer cells by regulating the expression of EMT markers, such as E-cadherin, ZO-1, vimentin, and N-cadherin. Importantly, we found that XIAP-AS1 knockdown significantly reduced STAT3 phosphorylation. Overall, this study suggests that lncRNA XIAP-AS1 might serve as a potential oncogene for colon cancer.

Pawelczyk K, Piotrowska A, Ciesielska U, et al.
Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The association between PD-L1 expression and clinicopathological features is still unclear. Therefore, we examined this relationship and also compare PD-L1 expression levels with Ki-67, p63 and TTF-1.
METHODS: 866 samples of NSCLCs were used to prepare tissue microarrays (TMAs) on which immunohistochemical (IHC) reactions were performed. Changes in the level of
RESULTS: PD-L1 expression was observed in 32.6% of NSCLCs. PD-L1 expression was increased in higher malignancy grades (G) (
CONCLUSIONS: PD-L1 expression seems to be associated with increased tumor proliferation and aggressiveness as well as shorter patient survival in NSCLC, predominantly in the AC group.

Hatano Y, Tamada M, Asano N, et al.
High-grade serous ovarian carcinoma with mucinous differentiation: report of a rare and unique case suggesting transition from the "SET" feature of high-grade serous carcinoma to the "STEM" feature.
Diagn Pathol. 2019; 14(1):4 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High-grade serous carcinoma, a representative high-grade ovarian carcinoma, is believed to be closely associated with a TP53 mutation. Recently, this category of ovarian carcinoma has gained increasing attention owing to the recognition of morphological varieties of TP53-mutated high-grade ovarian carcinoma. Herein, we report the case of a patient with high-grade serous carcinoma with mucinous differentiation.
CASE PRESENTATION: A 59-year-old postmenopausal woman was referred to the gynecologist because of abnormal vaginal bleeding. The radiological assessment revealed an intrapelvic multicystic mass, which was interpreted as an early right ovarian cancer and then removed by radical surgery. Histologically, the cancer cells were found in the bilateral ovaries and para-aortic lymph nodes. The cancer cells showed high-grade nuclear atypia and various morphologies, including the solid, pseudo-endometrioid, transitional cell-like (SET) pattern, and mucin-producing patterns. Benign and/or borderline mucin-producing epithelium, serous tubal intraepithelial carcinoma, and endometriosis-related lesions were not observed. In immunohistochemistry analyses, the cancer cells were diffuse positive for p53; block positive for p16; partial positive for WT1, ER, PgR, CDX2 and PAX8; and negative for p40, p63, GATA3, Napsin A, and vimentin. The Ki-67 labeling index of the cancer cells was 60-80%. Direct sequencing revealed that the cancer cells contained a missense mutation (c.730G>A) in the TP53 gene.
CONCLUSION: Mucinous differentiation in high-grade serous carcinoma is a rare and unique ovarian tumor phenotype and it mimics the phenotypes of mucinous or seromucinous carcinoma. To avoid the misdiagnosis, extensive histological and immunohistochemical analyses should be performed when pathologists encounter high-grade mucin-producing ovarian carcinoma. The present case shows that the unusual histological characteristic of high-grade serous carcinoma, the "SET" feature, could be extended to the solid, transitional, endometrioid and mucinous-like (STEM) feature.

Hong S, Xu J, Li Y, et al.
Topoisomerase IIβ-binding protein 1 activates expression of E2F1 and p73 in HPV-positive cells for genome amplification upon epithelial differentiation.
Oncogene. 2019; 38(17):3274-3287 [PubMed] Free Access to Full Article Related Publications
High-risk human papillomaviruses (HPVs) constitutively activate ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) DNA damage repair pathways for viral genome amplification. HPVs activate these pathways through the immune regulator STAT-5. For the ATR pathway, STAT-5 increases expression of the topoisomerase IIβ-binding protein 1 (TopBP1), a scaffold protein that binds ATR and recruits it to sites of DNA damage. TopBP1 also acts as a transcriptional regulator, and we investigated how this activity influenced the HPV life cycle. We determined that TopBP1 levels are increased in cervical intraepithelial neoplasias as well as cervical carcinomas, consistent with studies in HPV-positive cell lines. Suppression of TopBP1 by shRNAs impairs HPV genome amplification and activation of the ATR pathway but does not affect the total levels of ATR and CHK1. In contrast, knockdown reduces the expression of other DNA damage factors such as RAD51 and Mre11 but not BRCA2 or NBS1. Interestingly, TopBP1 positively regulates the expression of E2F1, a TopBP1-binding partner, and p73 in HPV-positive cells in contrast to its effects in other cell types. TopBP1 transcriptional activity is regulated by AKT, and treatment with AKT inhibitors suppresses expression of E2F1 and p73 without interfering with ATR signaling. Importantly, the levels of p73 are elevated in HPV-positive cells and its knockdown impairs HPV genome amplification. This demonstrates that p73, like p63 and p53, is an important regulator of the HPV life cycle that is controlled by the transcriptional activating properties of the multifunctional TopBP1 protein.

Dunn J, Ferluga S, Sharma V, et al.
Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism.
EBioMedicine. 2019; 40:77-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Meningioma is the most frequent primary intracranial tumour. Surgical resection remains the main therapeutic option as pharmacological intervention is hampered by poor knowledge of their proteomic signature. There is an urgent need to identify new therapeutic targets and biomarkers of meningioma.
METHODS: We performed proteomic profiling of grade I, II and III frozen meningioma specimens and three normal healthy human meninges using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. We validated differential expression of proteins and phosphoproteins by Western blot on a meningioma validation set and by immunohistochemistry.
FINDINGS: We quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades and normal meninges. Bioinformatics analysis revealed commonly upregulated proteins and phosphoproteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation studies confirmed significant overexpression of proteins such as EGFR and CKAP4 across all grades, as well as the aberrant activation of the downstream PI3K/AKT pathway, which seems differential between grades. Further, we validated upregulation of the total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Novel proteins identified and validated in meningioma included the nuclear proto-oncogene SET, the splicing factor SF2/ASF and the higher-grade specific protein, HK2, involved in cellular metabolism.
INTERPRETATION: Overall, we generated a proteomic thesaurus of meningiomas for the identification of potential biomarkers and therapeutic targets. FUND: This study was supported by Brain Tumour Research.

Li H, Ma N, Wang J, et al.
Nicotine Induces Progressive Properties of Lung Adenocarcinoma A549 Cells by Inhibiting Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Expression and Plasma Membrane Localization.
Technol Cancer Res Treat. 2018; 17:1533033818809984 [PubMed] Free Access to Full Article Related Publications
Lung cancer remains one of the most common cancer-related deaths worldwide. The cigarette smoking is a risk factor for lung cancer development. Interestingly, the cystic fibrosis transmembrane conductance regulator encoded by CFTR gene, an ATP-binding cassette transporter-class ion channel that conducts chloride and bicarbonate anions across membrane of epithelial cells, has recently been suggested to play a role in the development and progression of many types of cancer. It has been well-documented that mutations of CFTR gene are the cause of cystic fibrosis, the most common fatal hereditary lung disease in Caucasian population; the function of cystic fibrosis transmembrane conductance regulator in the development of lung cancer however has not yet been established. In the present study, we aimed to interrogate the impact of cystic fibrosis transmembrane conductance regulator on the nicotine-promoted progressive potency in lung adenocarcinoma cells by assessing capacities of cystic fibrosis transmembrane conductance regulator to cell migration, invasion, and clonogenicity and the expression of markers of cell proliferation and lung stem cell-related transcription factors in lung adenocarcinoma A549 cells. The exposure of nicotine exhibited an ability to enhance progressive properties of adenocarcinoma cells including A549 cells, HCC827 cells, and PC-9 cells, alone with an inhibition of cystic fibrosis transmembrane conductance regulator protein expression. Remarkably, an overexpression of cystic fibrosis transmembrane conductance regulator significantly inhibited the progressive potency of A549 cells, including capacity of cell migration and invasion and clonogenicity, along with a decreased expression of cell proliferative markers Ki67, p63, and proliferating cell nuclear antigen, and cancer stem cell marker CD133, stem cell pluripotency-related transcription factors octamer-binding transcription factor ¾, and sex-determining region Y-box 2, regardless of the presence of nicotine. In contrast, opposite effects were observed in A549 cells that the cystic fibrosis transmembrane conductance regulator was knockdown by short hairpin RNA to cystic fibrosis transmembrane conductance regulator. This study thus suggests that cystic fibrosis transmembrane conductance regulator may play a tumor suppressor role in lung cancer cells, which may be a novel therapeutic target warranted for further investigation.

Smirnov A, Lena AM, Cappello A, et al.
ZNF185 is a p63 target gene critical for epidermal differentiation and squamous cell carcinoma development.
Oncogene. 2019; 38(10):1625-1638 [PubMed] Related Publications
Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell-cell and cell-matrix adhesion programmes. However, limited knowledge exists on the relevant cell-cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell-cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell-cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.

Kang MK, Chen W, Park NH
Regulation of Epithelial Cell Proliferation, Differentiation, and Plasticity by Grainyhead-Like 2 During Oral Carcinogenesis.
Crit Rev Oncog. 2018; 23(3-4):201-217 [PubMed] Related Publications
Grainyhead-Like 2 (GRHL2) was originally described as one of the three mammalian isoforms with sequence homology to Grainyhead (GRH) in Drosophila, which determines the cuticle formation in fruit flies. Earlier studies characterized GRHL2 as an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Using a high-throughput proteomic approach, we discovered GRHL2 as a novel trans-regulator of the hTERT gene, which codes for the catalytic subunit of the human telomerase. GRHL2 was found to be necessary and sufficient for hTERT expression and telomerase activity in human oral squamous cell carcinomas (OSCCs) and in primary normal human keratinocytes. Subsequently, we found numerous other direct transcription targets of GRHL2, including p63, microRNA (miR)-200 family genes, FoxM1, and epidermal differentiation complex (EDC) genes. These target molecules mediate the phenotypic effects of GRHL2 on epithelial cell proliferation, differentiation, and epithelial plasticity. The pro-carcinogenic role of GRHL2 was implicated by its aberrant overexpression in OSCC cells and tissues, although several other studies also suggested the tumor suppressive effects of GRHL2. Using the novel Grhl2 cKO model, we recently reported the first genetic study in which Grhl2 knockout completely abolished oral carcinogenesis induced by a potent carcinogen, 4-nitroquinoline N-oxide (NQO). In this review, we discuss the mechanistic insights underlying the phenotypic effects of GRHL2 on epithelial cell proliferation and differentiation, as well as possibly mechanisms by which GRHL2 may promote oral carcinogenesis.

Rahman FU, Bhatti MZ, Ali A, et al.
Dimetallic Ru(II) arene complexes appended on bis-salicylaldimine induce cancer cell death and suppress invasion via p53-dependent signaling.
Eur J Med Chem. 2018; 157:1480-1490 [PubMed] Related Publications
A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))

Wang X, Chen H, Wen Y, et al.
Dicer affects cisplatin‑mediated apoptosis in epithelial ovarian cancer cells.
Mol Med Rep. 2018; 18(5):4381-4387 [PubMed] Free Access to Full Article Related Publications
Dicer is an essential enzyme that processes micro (mi)-RNA precursors into mature miRNAs, and serves a critical role in cancer development and progression by regulating gene expression. However, the role of Dicer in cisplatin‑mediated apoptosis and chemotherapy resistance in epithelial ovarian cancer (EOC) cells is poorly understood. In the present study, Dicer was expressed at low levels in cisplatin‑resistant A2780 cells when compared with parental cells. In addition, knocking down Dicer using short hairpin RNA decreased the sensitivity of A2780 and CAOV3 cells to cisplatin. Furthermore, downregulating Dicer significantly inhibited cisplatin‑induced apoptosis in ovarian cancer cells, and decreased the levels of proteins involved in apoptosis signaling pathways, including P73, P63, P53, caspase‑9 and caspase‑3. These findings indicated that Dicer may be a promising target for overcoming drug resistance in ovarian cancer.

Xia F, Ling W, Zhang J, et al.
Primary poorly differentiated lacrimal gland adenocarcinoma in left ocular region: A rare case report.
Medicine (Baltimore). 2018; 97(37):e12198 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Primary poorly differentiated lacrimal gland adenocarcinoma in the orbital region is an extremely rare type of neoplasm with only 1 related case in the literature. Its high grade of malignancy makes the timely data reported necessary. Hence, we present an extremely rare disease with biopsy results and recommendations on clinical treatment in an elderly male with Chinese descent.
PATIENT CONCERNS: A 66-year-old Chinese man presented with swelling in the left ocular region and eyeball proptosis. On physical examination, the patient had redness, tenderness, and swelling of the left eye. A surgical incision was noted on the left orbital region. Left eye movements were restricted.
DIAGNOSES: Immunohistochemical examination revealed pan-cytokeratin (PCK, +), p63 (partial, +), cytokeratin 7 (CK7, +), cytokeratin 14 (CK14, +), epithelial membrane antigen (EMA, +), protein expressed by erythroblast transformation-specific related gene (ERG, -), S-100 (, -), Epstein-Barr virus-encoded small RNA (EBER, -), smooth muscle actin (SMA, -), and Ki-67 (with a proliferation index approximately 40%). After carefully reviewed the manifestations, imaging findings, and immunohistochemical evidences, a diagnosis of poorly differentiated adenocarcinoma of lacrimal gland was made.
INTERVENTION: Based on the gene sequencing results, we started the patient with an intensive PF chemotherapy including a combination of cisplatine, fluorouracil, and epirubicin. Two months later, radiotherapy was introduced to the therapy regimen.
OUTCOMES: The patient responded well to the treatment without severe adverse events. MRI scan showed remarkable remission.
LESSONS: This rare case report will help raise the awareness of high grade lacrimal gland cancer, and subsequently aid the diagnosis in future cases. Positive immunohistochemical markers of CK7, CK14, EMA, p63, and high proliferation index of Ki-67 can help establishing a diagnosis, and cisplatine-fluorouracil program is proved feasible. We share the difficulties we have encountered, hoping to improve patient care in the future.

Suzuki A, Hirokawa M, Takada N, et al.
Utility of monoclonal PAX8 antibody for distinguishing intrathyroid thymic carcinoma from follicular cell-derived thyroid carcinoma.
Endocr J. 2018; 65(12):1171-1175 [PubMed] Related Publications
Follicular cell-derived thyroid carcinomas, including thyroid squamous cell carcinomas (SCCs) and anaplastic carcinomas, are immunoreactive for paired-box gene 8 (PAX8), while non-follicular cell-derived thyroid carcinomas stain negative for the PAX8 antibody. Intrathyroid thymic carcinoma (ITTC) arising from the intrathyroidal ectopic thymus exhibits moderate-to-strong nuclear reactivity for polyclonal PAX8. This is difficult to understand given that PAX8 is not associated with embryonic thymic development. We aimed to determine the diagnostic significance of monoclonal PAX8 antibody in distinguishing ITTCs from follicular cell-derived thyroid carcinomas. Ten ITTCs, 14 poorly differentiated thyroid carcinomas (PDTCs), 14 thyroid SCCs, 7 thymic tissue specimens, 7 thymomas, and 1 thymic carcinoma were analyzed using antibodies against polyclonal and monoclonal PAX8, thyroid transcription factor-1, p63, and CD5. Four ITTCs (40.0%) stained positive for polyclonal PAX8; none stained positive for monoclonal PAX8. All PDTCs and 92.9% of SCCs were immunoreactive for both polyclonal and monoclonal PAX8. All PDTCs, 46.2% of SCCs, and none of the ITTCs were immunoreactive for thyroid transcription factor-1. Eight ITTCs (80.0%), but none of the PDTCs and SCCs, were immunoreactive for CD5. We are the first to show that ITTCs stain negative for monoclonal PAX8. Monoclonal PAX8 is a more reliable marker than polyclonal PAX8 for determining follicular cell origin. We conclude that monoclonal PAX8 is a useful marker for distinguishing ITTCs from PDTCs and SCCs. Monoclonal PAX8 negativity is additional evidence in support of ITTCs not being follicular cell-derived thyroid carcinomas, but having a thymic origin.

Li X, Tian Z, Jin H, et al.
Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63α Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity.
Mol Cell Biol. 2018; 38(21) [PubMed] Free Access to Full Article Related Publications
Bladder cancer (BC) ranks as the sixth most common cancer in the United States and is the leading cause of death in patients with urinary malignancies. p63 is a member of the p53 family and is believed to function as a tumor suppressor in human BCs. Our most recent studies revealed a previously unknown function of the RING of XIAP in promoting microRNA 4295 (miR-4295) transcription, thereby reducing p63α protein translation and enhancing normal urothelial transformation, whereas p63α upregulates hsp70 transcription, subsequently activating the HSP70/Wasf3/Wave3/matrix metalloproteinase 9 (MMP-9) axis and promoting BC cell invasion via initiating the transcription factor E2F1. In this study, we found that p63α inhibited cyclin D1 protein expression, subsequently decreasing the ability of BC cell anchorage-independent growth

Shen Q, Wang H, Zhang L
Effect of exogenous p51a gene on the growth and chemo sensitivity of human lung adenocarcinoma cell lines.
Artif Cells Nanomed Biotechnol. 2018; 46(sup3):S383-S388 [PubMed] Related Publications
BACKGROUND: The dysfunction of p53-mediated apoptosis is the key to tumorigenesis, so most gene therapy programs concentrate on improving the expressing level of wild-type p53 in tumour cells. However, the p53 gene therapy has not yielded satisfactory results in tumours with normal p53 function. A new member of p53 gene family-p63, has provided new hopes. TAp63γ (p51A) resembles p53 the most, thus it might become a new promising therapeutic gene of tumours.
METHODS: We designed the primer pairs of p51A and amplified the p51A cDNA sequence from human skeletal muscle poly A + RNA to construct recombinant plasmid. It was then transfected into human lung adenocarcinoma cell lines A549 and NCI-H1299. RT-PCR, Western blot, MTT, flow cytometry and colony formation assay were used to analyse the growth and chemosensitivity of tumour cells.
RESULTS: The recombinant plasmid was constructed and transfected into tumour cells successfully. After transfection, p51A mRNA, P51A protein and P21 protein level raised significantly. Cell proliferation capacity and colony formation rate decreased while cell apoptosis rate and chemosensitivity to cisplatin and adriamycin increased significantly.
CONCLUSIONS: Exogenous p51A gene can increase its expression in A549 and NCI-H1299 cells, suppress cell growth and induce cell apoptosis. Moreover, it can also cooperate with chemotherapy and reduce the dose and side-effect. p51A gene can suppress tumours in spite of p53 status and p21 gene might be involved. It might become a new promising therapeutic gene of tumours, which will make up for the limitation of p53 gene therapy.

Chapman E, Skalova A, Ptakova N, et al.
Molecular Profiling of Hyalinizing Clear Cell Carcinomas Revealed a Subset of Tumors Harboring a Novel EWSR1-CREM Fusion: Report of 3 Cases.
Am J Surg Pathol. 2018; 42(9):1182-1189 [PubMed] Related Publications
We describe a novel gene fusion, EWSR1-CREM, identified in 3 cases of clear cell carcinoma (CCC) using anchored multiplex polymerase chain reaction, a next-generation sequencing-based technique. CCC is a low-grade salivary tumor recently characterized to have EWSR1-ATF1 fusions in the majority of cases. Three cases of malignant tumor presenting in the base of tongue, lung, and nasopharynx were studied. All cases shared a clear cell morphology with hyalinized stroma, presence of mucin and p63 positivity and were initially diagnosed as mucoepidermoid carcinoma but were negative for evidence of any of the expected gene fusions. Anchored multiplex polymerase chain reaction demonstrated a EWSR1-CREM fusion in all 3 cases to confirm a diagnosis of CCC. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. EWSR1-CREM fusions have not been previously reported in CCC and have only rarely been reported in other tumors. We show that the ability to discover novel gene variants with next-generation sequencing-based assays has clinical utility in the pathologic classification of fusion gene-associated tumors.

Suster D, Pihan G, Mackinnon AC, Suster S
Poorly Differentiated Nonkeratinizing Squamous Cell Carcinoma of the Thymus: Clinicopathologic and Molecular Genetic Study of 25 Cases.
Am J Surg Pathol. 2018; 42(9):1224-1236 [PubMed] Related Publications
Thymic carcinoma represents a rare and poorly understood type of thymic epithelial neoplasm that has been the subject of much controversy. Poorly differentiated nonkeratinizing squamous cell carcinoma, also known as lymphoepithelioma-like thymic carcinoma, is a rare variant of thymic carcinoma that has not been adequately characterized in the literature. The clinicopathologic, immunohistochemical, ultrastructural, and molecular features of 25 cases are reported. The patients were 19 men and 6 women, ranging in age from 20 to 85 years (mean: 60 y). The tumors presented clinically as anterior mediastinal masses with chest pain and shortness of breath or were found incidentally on imaging studies. Tumor size ranged from 2.0 to 13.5 cm in greatest diameter. Most of the tumors were small, well-circumscribed and confined to the mediastinum. Five cases presented with large, bulky, and infiltrative masses. Histologically, the hallmark of these tumors was a neoplastic proliferation of large, round to oval cells with vesicular nuclei, prominent eosinophilic nucleoli, and scant cytoplasm. Two histologic growth patterns were identified: tumors with a heavy lymphoplasmacytic stroma (lymphoepithelioma-like pattern), and tumors showing abundant desmoplastic stroma (desmoplastic pattern). Immunohistochemical stains showed strong positivity of the tumor cells for cytokeratin AE1/AE3, CK5/6, CK18, MOC31, p16, p40, and p63. MIB-1 showed on average 35% nuclear positivity. CD117 was positive in 21/25 cases and CD5 in 20/25 cases. Epstein-Barr encoded RNA in situ hybridization was positive in only 1 case. Electron microscopy in 4 cases showed primitive round to oval cells with prominent nucleoli, scant cytoplasm and immature cell junctions. Molecular features were studied by next-generation sequencing using high quality sequence data obtained from 18 patients. Variants with allele frequency between 5% and 45% and quality scores >50 were classified as somatic. A total of 16/18 cases had one or more somatic variants of unknown significance. One case showed an IDH1 p. R132C mutation, also of unknown significance. No "actionable" genes amenable to currently available targeted therapies were identified in this cohort. Clinical follow-up was obtained in 20 patients; 14 patients were alive and well with no evidence of disease between 1.5 and 16 years after diagnosis (median survival: 4 y; mean: 5.5 y). Most survivors had relatively small tumors (<5 cm. diameter), were in stage I and II at diagnosis and showed clear surgical margins. Five patients died of their tumors with metastases to bone, brain, chest wall, lungs and lymph nodes; all were in advanced stages and showed positive margins. Prognosis for these tumors appears to be correlated with the staging and status of the margins at the time of initial surgery.

Dudek AM, Vermeulen SH, Kolev D, et al.
Identification of an enhancer region within the TP63/LEPREL1 locus containing genetic variants associated with bladder cancer risk.
Cell Oncol (Dordr). 2018; 41(5):555-568 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Genome-wide association studies (GWAS) have led to the identification of a bladder cancer susceptibility variant (rs710521) in a non-coding intergenic region between the TP63 and LEPREL1 genes on chromosome 3q28, suggesting a role in the transcriptional regulation of these genes. In this study, we aimed to functionally characterize the 3q28 bladder cancer risk locus.
METHODS: Fine-mapping was performed by focusing on the region surrounding rs710521, and variants were prioritized for further experiments using ENCODE regulatory data. The enhancer activity of the identified region was evaluated using dual-luciferase assays. CRISPR/Cas9-mediated deletion of the enhancer region was performed and the effect of this deletion on cell proliferation and gene expression levels was evaluated using CellTiter-Glo and RT-qPCR, respectively.
RESULTS: Fine-mapping of the GWAS signal region led to the identification of twenty SNPs that showed a stronger association with bladder cancer risk than rs710521. Using publicly available data on regulatory elements and sequences, an enhancer region containing the bladder cancer risk variants was identified. Through reporter assays, we found that the presence of the enhancer region significantly increased ΔNTP63 promoter activity in bladder cancer-derived cell lines. CRISPR/Cas9-mediated deletion of the enhancer region reduced the viability of bladder cancer cells by decreasing the expression of ΔNTP63 and p63 target genes.
CONCLUSIONS: Taken together, our data show that bladder cancer risk-associated variants on chromosome 3q28 are located in an active enhancer region. Further characterization of the allele-specific activity of the identified enhancer and its target genes may lead to the identification of novel signaling pathways involved in bladder carcinogenesis.

Zinnall U, Weyerer V, Compérat E, et al.
Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype.
Hum Pathol. 2018; 80:55-64 [PubMed] Related Publications
Comprehensive molecular analyses of urothelial bladder cancer (UBC) have defined distinct subtypes with potential therapeutic implications. In this study, we focused on micropapillary urothelial carcinoma (MPUC), an aggressive, histomorphologically defined rare variant. Apart from genetic alterations shared with conventional UBC, alterations of the HER2 gene have been reported in higher frequencies. However, only small cohorts of MPUCs have been analyzed, and the real impact is still unclear. We collected a cohort of 94 MPUCs and immunohistochemically tested HER2, basal (CD44, CK5, EGFR, p63) and luminal (CD24, FOXA1, GATA3, CK20) markers to allocate MPUC to a molecular subtype. Additionally, HER2 amplification status was assigned by chromogenic in situ hybridization. Sanger sequencing of exon 4 and 8 was used to test for HER2 mutations. Kruskal-Wallis test was calculated to compare marker distribution between proportions of the MPUC component. HER2 2+/3+ staining scores were identified in 39.6% of 91 analyzed MPUCs and were not differentially distributed among the proportion of the MPUC component (P = .89). Additionally, CISH analysis revealed 30% of HER2-amplified tumors independently of the MPUC fraction. In 6/90 evaluable MPUCs, a p.S310F HER2 mutation was detected. Overexpression of luminal markers was observed in the majority of MPUC. Our investigations of the largest cohort of analyzed MPUC demonstrate that HER2 overexpression and amplifications are common genetic alterations and identification of overexpressed luminal markers allows subclassification to the luminal subtype. These findings highlight the need of histomorphological recognition of MPUC and analysis of HER2 status and the luminal molecular subtype for potential targeted therapeutic strategies.

Zhang L, Hu C, Zheng X, et al.
Oncocytic Schneiderian papilloma-associated adenocarcinoma and KRAS mutation: A case report.
Medicine (Baltimore). 2018; 97(23):e11025 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Oncocytic Schneiderian papillomas (OSP) are an uncommon type of sinonasal papillomas that arise from the Schneiderian epithelium, accounting for only 6% of all sinonasal papillomas. Malignancies arising in OSP are rare and are almost always described as in situ or invasive squamous cell carcinoma, although mucoepidermoid, small cell carcinoma and sinonasal undifferentiated carcinoma have also been reported. To our knowledge, only 18 such instances have been reported in the medical literature.
PATIENT CONCERNS: Here, we report the case of an 81-year-old man presenting with a left sinonasal neoplasm, who had undergone 4 operations. The first postoperative pathology revealed a benign nasal polyp. The following several postoperative pathology revealed a novel, human papillomavirus-negative adenocarcinoma with increasing malignant features with each recurrence arising in an OSP. In addition, the most recent recurrences were associated with metastasis of cervical lymph nodes. And after the operation, the patient refused adjuvant radiotherapy. On 6-month follow-up after the last operation, the patient developed an in situ tumor recurrence 1 month after the fourth operation and refused to undergo surgery again.
DIAGNOSIS: Immunohistochemistry for Ki67, CK7, CK5/6, P53, and P63 showed a progression of malignancy. HPV assay presented the 21 most prevalent HPV types were negative. In addition, KRAS gene exon 2 G12C presented mutation in the OSP-associated adenocarcinoma.
INTERVENTIONS: During the whole course of the patient's disease, we performed four nasal endoscopic operations. And after the last operation, the patient refused adjuvant radiotherapy and KRAS-targeted therapy.
OUTCOMES: We are the first to describe adenocarcinoma arising in an OSP. To our surprise, from the first benign neoplasm to the second OSP-associated adenocarcinoma, it went through a long period of 10 years. However, after the adenocarcinogenesis, the differentiation of tumor became worse with the shorter interval of each recurrence.
LESSONS: Therefore, for elderly patients with unilateral nasal polyps, long-term follow-up is necessary. Once OSP turns into malignant, radical resection should be performed as much as possible to reduce the irritability of tumors.

Luo G, Xia X, Wang X, et al.
miR-301a plays a pivotal role in hypoxia-induced gemcitabine resistance in pancreatic cancer.
Exp Cell Res. 2018; 369(1):120-128 [PubMed] Related Publications
Hypoxia is a hallmark of pancreatic cancer (PC) and is associated with gemcitabine resistance. However, the mechanisms underlying hypoxia-induced gemcitabine resistance in PC remain greatly unknown. Our previous work showed that miR-301a, a hypoxia-sensitive miRNA, is involved in PC metastasis under hypoxia via regulation of its target gene P63. Here, we showed that miR-301a was upregulated in a NF-κB independent manner and promoted gemcitabine resistance under hypoxic conditions in vitro. In addition, TAp63, a member of the P63 family, reversed hypoxia-induced gemcitabine resistance by promoting degradation of HIF-1α. Furthermore, we proved that TAp63 was a functional downstream target of miR-301a and mediated the biological properties of miR-301a in PC. Taken together, these findings indicate that miR-301a exerts as a critical regulator involved in hypoxia-induced gemcitabine resistance in PC and may have potentials to be a therapeutic target for PC patients.

Sato A, Ueno H, Fusegi M, et al.
A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells.
Pharmacology. 2018; 102(1-2):26-36 [PubMed] Related Publications
BACKGROUND: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1).
METHODS: WST-1 and cell analyzers were employed to analyze the effects of T3E on cell viability and apoptosis of human MM cell lines (H2452, H28). Real-time PCR and Western blot were performed to evaluate the expression at mRNA and protein levels. Methylation status and epigenetic modifications of DKK1's promoter regions after T3E treatment in MM cells were studied using methylation-specific PCR and Chromatin immunoprecipitation. Small interfering RNA-mediated knockdown -(siRNA), and specific inhibitors, were used to validate DKK1 as a target of T3E.
RESULTS: T3E markedly impaired MM cell viability, increased the expression of phosphorylated-JNK and DKK1 and suppressed cyclin D, a downstream target gene of Wnt signaling. Knockdown of DKK1 expression by siRNA or a specific JNK inhibitor confirmed the contribution of DKK1 and JNK to T3E-induced cytotoxicity in MM cells. On the other hand, cytoskeleton-associated protein 4 (CKAP4) expression, which promotes cell proliferation as a Wnt-independent DKK1 receptor was inhibited by T3E. Silencing CKAP4 by -siRNA did not appear to directly affect MM cell viability, thereby indicating that expression of both DKK1 and CKAP4 is required. Furthermore, T3E-mediated inhibition of both DNA methyltransferases (DNMT1, 3A, and 3B) and histone deacetylases (HDAC1, 2, 3, and 8) in MM cells leads to increased DKK1 expression, thereby promoting tumor growth inhibition. MM cells treated with Zebularine (a DNMT inhibitor) and sodium butyrate (an HDAC inhibitor) exhibited cytotoxic effects, which may explain the inhibitory action of T3E on MM cells. In addition, an enhanced expression of DKK1 in MM cells following T3E treatment is positively correlated with the methylation status of its promoter; T3E decreased DNA methylation and increased histone acetylation. Moreover, T3E specifically increased histone H3 lysine 4 (H3K4) methylation activity, whereas no effects were observed on histone H3K9 and H3K27.
CONCLUSIONS: Targeting the epigenetic induction of DKK1 may lead to effective treatment of MM, and T3E has great potential to induce anti-MM activity.

Torres A, Alshalalfa M, Davicioni E, et al.
ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63.
Prostate. 2018; 78(12):896-904 [PubMed] Related Publications
BACKGROUND: Rare prostate carcinomas aberrantly express p63 and have an immunophenotype intermediate between basal and luminal cells. Here, we performed gene expression profiling on p63-expressing prostatic carcinomas and compared them to usual-type adenocarcinoma. We identify ETS2 as highly expressed in p63-expressing prostatic carcinomas and benign prostate basal cells, with lower expression in luminal cells and primary usual-type adenocarcinomas.
METHODS: A total of 8 p63-expressing prostate carcinomas at radical prostatectomy were compared to 358 usual-type adenocarcinomas by gene expression profiling performed on formalin fixed paraffin embedded tumor tissue using Affymetrix 1.0 ST microarrays. Correlation between differentially expressed genes and TP63 expression was performed in 5239 prostate adenocarcinomas available in the Decipher GRID. For validation, ETS2 in situ hybridization was performed on 19 p63-expressing prostate carcinomas and 30 usual-type adenocarcinomas arrayed on tissue microarrays (TMA).
RESULTS: By gene expression, p63-expressing prostate carcinomas showed low cell cycle activity and low Decipher prognostic scores, but were predicted to have high Gleason grade compared to usual-type adenocarcinomas by gene expression signatures and morphology. Among the genes over-expressed in p63-expressing carcinoma relative to usual-type adenocarcinoma were known p63-regulated genes, along with ETS2, an ETS family member previously implicated as a prostate cancer tumor suppressor gene. Across several cohorts of prostate samples, ETS2 gene expression was correlated with TP63 expression and was significantly higher in benign prostate compared to usual-type adenocarcinoma. By in situ hybridization, ETS2 gene expression was high in benign basal cells, and low to undetectable in benign luminal cells or usual-type adenocarcinoma. In contrast, ETS2 was highly expressed in 95% (18/19) of p63-expressing prostate carcinomas.
CONCLUSIONS: ETS2 is a predominantly basally-expressed gene in the prostate, with low expression in usual-type adenocarcinoma and high expression in p63-expressing carcinomas. Given this pattern, the significance of ETS2 loss by deletion or mutation in usual-type adenocarcinomas is uncertain.

Zhong Y, Liu L, Qi B, et al.
The screening and electron microscopy observation of mammary analogue secretory carcinoma in Chinese.
J Craniomaxillofac Surg. 2018; 46(6):893-897 [PubMed] Related Publications
Mammary analogue secretory carcinoma of salivary gland (MASC) is a tumor with histopathologic and immunophenotypic features mimicking secretory carcinoma of the breast harboring the ETV6 split. The expression of mammaglobin, S-100, Ki-67, P63 and ETV6 split were detected in twelve cases of acinar cell carcinoma and fourteen cases of mammary analogue secretory carcinoma of salivary gland by immunohistochemistry and fluorescence in situ hybridization respectively. The expression of ETV6 gene split was detected in fourteen mammary analogue secretory carcinomas of salivary gland with positive expression of mammaglobin. Eight of mammary analogue secretory carcinomas of salivary gland also tested positive for the ETV6 gene split via fluorescence in-situ hybridization (FISH). The concordance rate of the immunohistochemistry and FISH was 72.3%. Mammaglobin and ETV6 gene split detection could help to distinguish mammary analogue secretory carcinoma of salivary gland. The mammary analogue secretory carcinoma of salivary gland specimens were also examined under transmission electron microscope. And apical junctional complexes were observed in the loosely connected tumor cells.

Rokudai S, Li Y, Otaka Y, et al.
STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis.
Proc Natl Acad Sci U S A. 2018; 115(21):E4806-E4814 [PubMed] Related Publications
Levels of the N-terminally truncated isoform of p63 (ΔN p63), well documented to play a pivotal role in basal epidermal gene expression and epithelial maintenance, need to be strictly regulated. We demonstrate here that the anaphase-promoting complex/cyclosome (APC/C) complex plays an essential role in the ubiquitin-mediated turnover of ΔNp63α through the M-G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to ΔNp63, can suppress the APC/C-mediated proteolysis of ΔNp63. Supporting the physiological relevance, of these interactions, both Stxbp4 and an APC/C-resistant version of ΔNp63α (RL7-ΔNp63α) inhibit the terminal differentiation process in 3D organotypic cultures. In line with this, both the stable RL7-ΔNp63α variant and Stxbp4 have oncogenic activity in soft agar and xenograft tumor assays. Notably as well, higher levels of Stxbp4 expression are correlated with the accumulation of ΔNp63 in human squamous cell carcinoma (SCC). Our study reveals that Stxbp4 drives the oncogenic potential of ΔNp63α and may provide a relevant therapeutic target for SCC.

Agaimy A, Fonseca I, Martins C, et al.
NUT Carcinoma of the Salivary Glands: Clinicopathologic and Molecular Analysis of 3 Cases and a Survey of NUT Expression in Salivary Gland Carcinomas.
Am J Surg Pathol. 2018; 42(7):877-884 [PubMed] Free Access to Full Article Related Publications
NUT carcinoma (NC) represents a rare subset of highly aggressive poorly differentiated carcinomas characterized by rearrangement of the NUT (aka NUTM1, nuclear protein in testis) gene, most commonly fused to BRD4. Originally described as a mediastinal/thymic malignancy, NC has been reported at a variety of anatomic regions including the upper and lower aerodigestive tract. To date, only 7 NC cases of probable salivary gland origin have been reported. We herein describe 3 new cases (all affecting the parotid gland) in 2 women (39- and 55-y old) and 1 man (35-y old). Histologic examination showed poorly differentiated neoplasms composed of poorly cohesive small-sized to medium-sized cells with variable squamoid cell component that was focal and abrupt. Immunohistochemistry showed uniform expression of p63 and distinctive punctate expression of the NUT antigen in the tumor cell nuclei. Review of the reported salivary gland NC cases (total, 10) showed a male:female ratio of 1.5:1 and an age range of 12 to 55 years (median, 29 y). Site of the primary tumor was the parotid (7), sublingual (2), and submandibular (1) glands. All presented as rapidly growing masses treated by surgery followed by adjuvant radiotherapy/chemotherapy. Initial nodal status was positive in 8/10. At last follow-up (1 to 24 mo; median, 5 mo), 7/10 patients died of disease at a median of 5.5 months (1 to 24 mo) and only 2 were disease free at 7 and 14 months. Of 9 cases with genetic data, the fusion partner was BRD4 (n=7), non-BRD4/3 (n=1), or undetermined (n=1). None of 306 carcinomas spanning the spectrum of salivary carcinoma types screened by NUT immunohistochemistry was positive. This is the first small series on salivary NC highlighting the importance to include this rare disease in the differential diagnosis of poorly differentiated salivary gland carcinomas and in cases of presumable poorly differentiated carcinoma of unknown origin.

Righi A, Sbaraglia M, Gambarotti M, et al.
Extra-axial chordoma: a clinicopathologic analysis of six cases.
Virchows Arch. 2018; 472(6):1015-1020 [PubMed] Related Publications
Extra-axial chordoma is an exceedingly rare tumor, with only 28 cases reported in the literature to date. Axial and extra-axial chordoma exhibits complete morphologic and immunophenotypic (expression of brachyury) overlap. However, in consideration of the non-canonical presentation, extra-axial chordoma is under-recognized and often misdiagnosed, most often as extraskeletal myxoid chondrosarcoma or myoepithelioma. To increase our understanding of the clinicopathologic features of extra-axial chordoma, six cases have been retrieved from the files of the Istituto Ortopedico Rizzoli and of the General Hospital of Treviso. The clinicoradiologic, morphologic, and molecular features have been analyzed, and the follow-up was updated. Our series included four female and two male patients; their ages ranged from 20 to 67 years (mean 45.8 years). All patients presented with a single mass localized in four cases in the soft tissue (posterior arm, left leg, dorsal aspect of the foot, and popliteal fossa), and in two cases in the bone (radius and second metacarpal bone). Grossly, the neoplasm was lobulated, with a fleshy cut surface and a diameter ranging between 0.8 and 8 cm (mean 3.4 cm). Morphologically, all six cases showed an epithelioid cell proliferation organized in nests and cords demarcated by fibrous septa and set in an abundant extracellular myxoid matrix. Neoplastic cells featured hyperchromatic nuclei and abundant vacuolated cytoplasm. Immunohistochemically, all six cases were strongly positive for EMA, cytokeratin AE1/AE3, S100, and brachyury. INI1 nuclear expression was retained. Smooth muscle actin, calponin, p63, and GFAP were all negative. Fluorescent in situ hybridization (FISH) analysis did not reveal rearrangements involving NR4A3, FUS, and EWSR1 genes. At follow-up (mean 55 months), all patients were alive without disease after local surgical treatment. One patient underwent thigh amputation following multiple local recurrences and inguinal node metastases treated with marginal resection. In conclusion, primary extra-axial chordoma is an extremely rare neoplasm with distinct morphological and immunohistochemical features. Immunomorphology and molecular analysis allow distinction from both extraskeletal myxoid chondrosarcoma and myoepithelioma. Complete surgical resection appears to be curative.

David SN, Arnold Egloff SA, Goyal R, et al.
MAGI2 is an independent predictor of biochemical recurrence in prostate cancer.
Prostate. 2018; 78(8):616-622 [PubMed] Related Publications
BACKGROUND: Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) promotes the activity of phosphatase and tensin homolog (PTEN). Recent studies suggest that dysregulation of this signaling pathway has a role in prostate carcinogenesis. Our study aims to determine the prognostic significance of MAGI2 expression in prostate cancer.
METHODS: Tissue microarrays from 51 radical prostatectomy cases including benign prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma were constructed. Immunohistochemistry with double staining for MAGI2 and p63 was performed and analyzed by image analysis as percent of analyzed area (%AREA). Multivariable logistic regression was used to correlate MAGI2 expression with clinical outcomes. Generalized Estimating Equations (GEE) with linear and logistic regression was used to correlate MAGI2 with intrapatient histology.
RESULTS: MAGI2 %AREA was inversely associated with progression from HGPIN to adenocarcinoma of low to high Gleason score (OR, 0.980; slope, -0.02; P = 0.005) and HGPIN to cancer of any Gleason score (OR, 0.969; P = 0.007). After adjusting for grade, stage, and margin status, MAGI2 %AREA was a significant independent predictor of biochemical recurrence (BCR) (OR, 0.936; 95%CI, 0.880-0.996; P = 0.037; bootstrap P = 0.017). The addition of MAGI2 %AREA to these standard clinical parameters improved accuracy of predicting BCR by 2.9% (91.0% vs 88.1%).
CONCLUSIONS: These results reveal that MAGI2 expression is reduced during prostate cancer progression and that retention of MAGI2 signal reduces odds of BCR. The study results further suggest a possible role of MAGI2 in prostate neoplasia. Decreased MAGI2 expression may help predict prostate cancer aggressiveness and provide new insight for treatment decisions and post-operative surveillance intervals.

Andricovich J, Perkail S, Kai Y, et al.
Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors.
Cancer Cell. 2018; 33(3):512-526.e8 [PubMed] Free Access to Full Article Related Publications
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

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