The cyclin-dependent kinase inhibitor p57 KIP2 is thought to be a potential tumor suppressor gene (TSG). The present study examines this possibility. We found that the expression of p57 KIP2 gene is absent in various hematological cell lines. Exposing cell lines to the DNA demethylating agent 5-aza-2-deoxycytidine restored p57 KIP2 gene expression. Bisulfite sequencing analysis of its promoter region showed that p57 KIP2 DNA was completely methylated in cell lines that did not express the p57 KIP2 gene. Thus, DNA methylation of its promoter might lead to inactivation of the p57 KIP2 gene. DNA methylation of this region is thought to be an aberrant alteration, since DNA was not methylated in normal peripheral blood mononuclear cells or in reactive lymphadenitis. Methylation-specific polymerase chain reaction analysis found frequent DNA methylation of the p57 KIP2 gene in primary diffuse large B-cell lymphoma (54.9%) and in follicular lymphoma (44.0%), but methylation was infrequent in myelodysplastic syndrome and adult T-cell leukemia (3.0% and 2.0%, respectively). These findings directly indicate that the profile of the p57 KIP2 gene corresponds to that of a TSG. IntroductionCell cycle progression is promoted by cyclins and cyclindependent kinases (CDKs) and is counterbalanced by CDK inhibitors. 1 These components are regulated in the normal cell cycle, and disrupted regulation is closely related to tumorigenesis. For example, activation of cyclin D1 by bcl-1 translocation (t(11; 14)(q13;q23)) is a critical genetic alteration in mantle cell lymphoma, 2,3 and the CDK inhibitor p16 INK4A is genetically lost or mutated in many malignancies. 4 CDK inhibitors have been categorized into 2 families. One family, inhibitors of CDK4 (INK4s), includes p16 and p15, has repeated ankyrinlike sequences, and is a specific inhibitor of CDK4 and CDK6, resulting in competing cyclin D. 5,6 The other family, kinase inhibitor proteins (KIPs), includes p21 CIP1 , p27 KIP1 , and p57 KIP2 , 7-10 and this family potently inhibits the binding of several cyclin/CDK complexes. The presence of mutations and deletions in INK4s indicates that they are tumor suppressor genes (TSGs) 4 and that their function as negative regulators of cell proliferation fits the profile of TSGs. Because the KIP family also consists of CDK inhibitors, genetic alterations of the p21 CIP1 gene 11 and p57 KIP2 genes 12-14 have been extensively studied. In particular, the p57 KIP2 gene is located at chromosome 11p15.5, a region implicated in sporadic cancers, including those of the breast, 15 liver, 16 and bladder. 17 Beckwith-Wiedemann syndrome (BWS), 18 which is characterized by the somatic overgrowth of various tissues, including the kidneys, liver, and skeletal muscle, and by a predisposition to embryonal tumors of these organs (Wilms tumor, hepatoblastoma, and embryonal rhabdomyosarcoma), is linked to this region. 19 Although germ line point mutations of the p57 KIP2 gene resulting in protein truncation have been identified in some patients with BWS, 20,21 so...
Previously, we used the reverse transcription-polymerase chain reaction (RT-PCR) to show that mammaglobin (MGB1) can serve as a differential marker of breast cancer metastasis from primary lung cancer. However, mRNA-based methods are not appropriate for use in clinical practices. In this study, we examined MGB1 protein expression in 480 tumors from various organs using immunohistochemical detection and a tissue microarray technique. Breast cancers expressing MGB1 were also analyzed clinicopathologically to determine whether these cancers constitute a characteristic subset. Immunohistochemically, MGB1 was expressed specifically in breast cancers. Of the other cancers examined, including 29 of the head and neck, eight of the thyroid, 106 of the lung, 35 of the gastrointestinal tract, three of the pancreas, 14 of the uterine cervix and 13 of the ovary, none were positive for MGB1 except a proportion of salivary gland tumors (6/11, 55%) and endometrial cancers (3/23, 13%). Among the 238 breast cancers, MGB1 was expressed in 114 (48%), most of which were classified histologically as invasive duct or lobular carcinomas. Clinicopathologically, MGB1 expression was associated with positive expression of estrogen receptors and negative expression of CK5, but not with pathological stage, HER2 gene amplification or p53 immunoreactivity. Kaplan-Meier analysis revealed prolonged disease-free survival in patients with MGB1-positive breast cancers (log rank test, P ¼ 0.016), but the Cox proportional hazard model failed to confirm that MGB1 was an independent prognostic factor (hazard ratio 1.77, P ¼ 0.1755). In terms of practical diagnosis, MGB1 immunohistochemistry can serve as a differential marker of breast cancer metastasis from primary lung cancer for two reasons. Firstly, HER2-positive breast cancer frequently lacks estrogen receptor expression, but MGB1 is expressed in about half of this subtype. Secondly, as primary lung adenocarcinomas may express estrogen receptors, MGB1 expression provides further discrimination of the origin of breast cancers.
, CD20؊ large B-cell lymphoma, she was treated with conventional combination chemotherapies. However, the lymphoma was primarily chemotherapy resistant, and the patient died 11 months after admission. We consider that this case confirms the existence of ALK
c-Maf translocation or overexpression has been observed in human multiple myeloma. Although c-maf might function as an oncogene in multiple myeloma, a role for this gene in other cancers has not been shown. In this study, we have found that mice transgenic for c-Maf whose expression was direct to the T-cell compartment developed T-cell lymphoma. Moreover, we showed that cyclin D2, integrin B 7 , and ARK5 were upregulated in c-Maf transgenic lymphoma cells. Furthermore, 60% of human T-cell lymphomas (11 of 18 cases), classified as angioimmunoblastic T-cell lymphoma, were found to express c-Maf. These results suggest that c-Maf might cause a type of T-cell lymphoma in both mice and humans and that ARK5, in addition to cyclin D2 and integrin B 7 , might be downstream target genes of c-Maf leading to malignant transformation.
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