Proteins of the retinoblastoma pathway,FEN1 and MGMT are novel potential prognostic biomarkers in pancreatic adenocarcinoma

Background

We studied the expression of some major proteins involved in cell-cycle regulation and DNA repair, the roles of which are not well known in pancreatic ductal adenocarcinoma (PDAC), but which have a significant impact on carcinogenesis of many other cancers.

细胞周期类分子在人无精子症睾丸中的表达

目的:评价细胞周期类基因在人无精子症及正常睾丸组织中的表达及意义.方法:应用包含有人CDC10等细胞周期类基因在内的cDNA微矩阵芯片对人正常睾丸及无精子症睾丸组织中差异表达基因进行了研究:通过PCR方法获得两种组织mRNA, 再分别用Cy5-dUTP及Cy3-dUTP标记制备cDNA探针.两种探针混合后与人cDNA微矩阵芯片杂交, 经扫描、计算机处理分析比较杂交结果;利用原位杂交技术对芯片杂交结果进行了验证研究.结果:部分细胞周期类基因可能与无精子症相关, 其中CDC7L1 与CDC10基因表达上调, CDK9、 CDC20 以及CLK3基因表达下调.原位杂交证实CDC10在正常睾丸组织生精细胞中表达强于无精子症睾丸组织.结论:细胞周期类分子CDC10、 CDC7L1 、 CDK9、 CDC20及CLK3可能在无精子症的发生与进展过程中起一定的作用.     

Characterization of de novo microdeletions involving 17q11.2q12 identified through chromosomal comparative genomic hybridization

High-resolution array-comparative genome hybridization (CGH) is a powerful tool for detection of submicroscopic chromosome deletions and duplications. We describe two patients with mild mental retardation (MR) and de novo microdeletions of 17q11.2q12. Although the deletions did not involve the neurofibromatosis type 1 (NF1) gene, they overlap with long-range deletions of the NF1 region which have been encountered in a small group of NF1 patients with more severe MR. Given the overlap of the deletions in our two patients with the large-sized NF1 microdeletions but not with the more frequent and smaller NF1 deletions, we hypothesize that more than one gene in the 17q11.2q12 region may be involved in MR. We discuss candidate genes for MR within this interval that was precisely defined through array-CGH analysis.     

Dedifferentiated low-grade central osteosarcoma with extensive cystic change initially treated as a simple bone cyst

Low-grade central osteosarcoma (LG-COS) is an uncommon variant of osteosarcoma (OS) that sometimes progresses to high-grade OS post-recurrence. We herein present a case of dedifferentiated LG-COS with extensive cystic change arising in the right iliac bone of a 26-year-old man. The LG-COS was initially diagnosed and managed as a simple bone cyst. The lesion recurred thrice, and high-grade OS was diagnosed during the third recurrence. The first lesion appeared as a typical benign cystic mass on radiography. However, a huge malignant osteoblastic mass subsequently developed in the right pelvis at the third recurrence. Extended hemipelvectomy with ipsilateral hemisacral resection was performed. Histologic analysis showed tumor necrosis and irregular neoplastic tumor osteoid, while immunohistochemistry revealed that the tumor was diffusely positive for MDM2 and CDK4. The histologic diagnosis was high-grade OS dedifferentiated from a preceding cystic lesion. Our final diagnosis of the primary lesion was LG-COS with extensive cystic change.     

Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity

Inflammatory malignant fibrous histiocytoma (inflammatory MFH) is a very rare tumour that occurs most often in the retroperitoneum. So far, it has been considered to be a special subtype of MFH. As it is now widely accepted that most retroperitoneal pleomorphic MFHs are dedifferentiated liposarcomas, the present study compared histological features, genomic profile (CGH analysis), and MDM2 and CDK4 status (immunohistochemistry, FISH, and quantitative PCR) in inflammatory MFHs from 12 patients and dedifferentiated liposarcomas that had an inflammatory MFH component from eight patients. Metaphase cytogenetic and FISH analyses were also performed on one inflammatory MFH. Histological review showed areas of well-differentiated liposarcoma in nine inflammatory MFHs. CGH analysis showed 12q13-15 amplification or gain in six of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Immunohistochemistry showed positivity of tumour cells for MDM2 in every tumour in both groups and for CDK4 in ten and seven inflammatory MFHs and dedifferentiated liposarcomas, respectively. Metaphase cytogenetic and FISH analysis performed on one inflammatory MFH showed the presence of a supernumerary large marker chromosome and ring chromosome with high-level amplification of both MDM2 and CDK4 genes. FISH analysis on paraffin wax-embedded sections showed amplifications of MDM2 and CDK4 in seven of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Quantitative PCR showed amplification of MDM2 in six and of CDK4 in seven of nine inflammatory MFHs. In conclusion, this study strongly suggests that most so-called inflammatory MFHs are dedifferentiated liposarcomas.     

CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation

CDK9 is a member of the CDC2-like family of kinases. Its cyclin partners are members of the CYCLIN T family (T1, T2a, and T2b) and CYCLIN K. The CDK9/CYCLIN T1 complex is very important in the differentiation programme of several cell types, controlling specific differentiation pathways. Limited data are available regarding the expression of CDK9/CYCLIN T1 in haematopoietic and lymphoid tissues. The aim of this study was to analyse the expression of the CDK9/CYCLIN T1 complex in lymphoid tissue, in order to assess its role in B- and T-cell differentiation and lymphomagenesis. CDK9/CYCLIN T1 expression was found by immunohistochemistry in precursor B and T cells. In peripheral lymphoid tissues, germinal centre cells and scattered B- and T-cell blasts in interfollicular areas expressed CDK9/CYCLIN T1, while mantle cells, plasma cells, and small resting T-lymphocytes displayed no expression of either molecule. CDK9/CYCLIN T1 expression therefore appears to be related to particular stages of lymphoid differentiation/activation. CDK9 and CYCLIN T1 were highly expressed in lymphomas derived from precursor B and T cells, from germinal centre cells, such as follicular lymphomas, and from activated T cells (ie anaplastic large cell lymphomas). Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma also showed strong nuclear staining. Diffuse large B-cell, Burkitt's lymphomas, and peripheral T-cell lymphomas, among T-cell lymphoproliferative disorders, showed a wide range of values. No expression of CDK9 or CYCLIN T1 was detected in mantle cell and marginal zone lymphomas. However, at the mRNA level, an imbalance in the CDK9/CYCLIN T1 ratio was found in follicular lymphoma and diffuse large B-cell lymphomas with germinal centre phenotype, and in the cell lines of classical Hodgkin's lymphomas, Burkitt's lymphomas, and anaplastic large cell lymphoma, in comparison with reactive lymph nodes. These results suggest that the CDK9/CYCLIN T1 complex may affect the activation and differentiation programme of lymphoid cells. The molecular mechanism through which the CDK9/CYCLIN T1 complex is altered in malignant transformation needs to be elucidated.     

CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia

The CDKN2A gene has been implicated in cutaneous malignant melanoma (CMM) in about 40% of families with linkage to chromosome 9p21, while a small proportion of families have mutations in the CDK4 gene. In order to estimate the importance of these genes in the predisposition to CMM in Spanish families and patients we have analysed, by SSCA, a total of 56 subjects belonging to 34 CMM families, and nine patients with multiple CMM and other neoplasia. We have detected germline CDKN2A mutations in six out of the 34 families (17%). A frameshift mutation (358delG) and four missense mutations (G59V, G101W (two cases), D84Y, and R87W) were identified. Five CMM patients from different families (14%) carried the A148T variant, which is known not to affect p16 activity. No mutations were detected in the patients with multiple CMM or other neoplasms. We have not found mutations either in exon 1 beta of the CDKN2A gene or in exon 2A of CDK4. Linkage analysis of the 9p21 region showed exclusion for one of the families for CMM and for four families for CMM/dysplastic naevi. This study indicates a small role for CDKN2A in Spanish CMM families and suggests that other genes are also responsible for CMM predisposition.     

血小板第4因子对辐射损伤小鼠骨髓细胞周期的调控机制

目的：检测小鼠骨髓细胞p53、Cyclin D1及CDK4蛋白表达量的变化，以探讨血小板第4因子（PF4）对急性辐射损伤小鼠骨髓细胞保护作用的机制。方法：雄性BALB／c小鼠随机分为3组，第1组（正常对照组）、第2组（单纯照射组）、第3组（PF4保护组），第3组在照射前26h及20h腹腔注射PF440μg／kg，第2、3组全身一次性5Gy ^60Co-γ射线照射，照射后4h取小鼠骨髓细胞，Western blot检测小鼠骨髓细胞内p53、Cyclin D1、CDK4蛋白量表达的变化。结果：第2组、第3组小鼠骨髓细胞p53蛋白量与第1组相比明显升高，而Cyclin D1、CDK4则明显降低（P〈0．05）；第2组与第3组p53蛋白表达量的表达有明显差异（P〈0．05），而Cyclin D1与CDK4无统计学意义（P〉0．05）。结论：p53蛋白在PF4对急性辐射损伤小鼠骨髓细胞周期调控作用中起一定作用。     

Dedifferentiated liposarcoma of the spermatic cord with a hemangioendothelioma-like component: A case report and review of the literature

Atypical lipomatous tumor or well-differentiated liposarcoma/dedifferentiated liposarcoma (DDLPS) is the most frequent subtype of malignant adipocytic tumor. This tumor typically presents in late adult life, most commonly in the retroperitoneum, extremities, or spermatic cord. It has been reported that the dedifferentiated component consists mainly of high-grade sarcoma, including undifferentiated pleomorphic sarcoma, fibrosarcoma, and myxofibrosarcoma, and it has been recently reported that the dedifferentiated component can be also made up of a low-grade sarcomatous component. Therefore, the dedifferentiated areas exhibit a wide morphological spectrum that commonly includes fibroblastic/myofibroblastic and fibrohistiocytic tumors but very rarely includes vascular tumors. We present here the first reported case of DDLPS with a hemangioendothelioma-like component in the spermatic cord.     

Zinc finger of the cerebellum 5 promotes colorectal cancer cell proliferation and cell cycle progression through enhanced CDK1/CDC25c signaling

IntroductionColorectal cancer (CRC), mostly caused by external or environmental factors, is the third most common and lethal cancer worldwide. Although a large number of investigations have been carried out to reveal the evolution of CRC, the underlying mechanisms of CRC remain unclear.Material and methodsExpression of zinc finger of the cerebellum 5 (ZIC5) in CRC tissues and cell models was measured by qRT-PCR and IHC. Cell transfection was carried out for ZIC5 overexpression or knockdown. The MTT assay was applied to examine the capacity of glioma cell proliferation. Wound healing assay and tumor invasion assay were used to test the capacity of glioma cell migration and invasion respectively. Cell cycle analysis and western blot were used to verify the apoptosis rates of CRC cells upon ZIC5 overexpression or downregulation. A further tumor Xenograft study was used to examine the effects of ZIC5 on tumor malignancy in vivo.ResultsCell models using HCT116 and SW620 cells were established to study the ZIC5 function upon ZIC5 overexpression of knockdown. Consistently, we discovered that ZIC5 also significantly increased in Chinese CRC patients. In addition, ZIC5 promoted CRC cell proliferation through increasing the proportion of cells maintained in the S phase. ZIC5 overexpression facilitated the capacity of CRC cell migration and invasion. Inhibition of ZIC5 mitigated such malignant effects.ConclusionsCollectively, investigations of the ZIC5 in CRC provided a new insight into CRC diagnosis, treatment, prognosis and next-step translational therapeutic developments from bench to clinic.