Biomedical subjects

Hiroshi Kamma

Publications and source records attributed to Hiroshi Kamma.

At least 19 recordsLinked to original sources

PubMed2006

Breast disease: clinical application of US elastography for diagnosis.

PURPOSE: To evaluate the diagnostic performance of real-time freehand elastography by using the extended combined autocorrelation method (CAM) to differentiate benign from malignant breast lesions, with pathologic diagnosis as the reference standard. MATERIALS AND METHODS: This study was approved by the University of Tsukuba Human Subjects Institutional Review Board; all patients gave informed consent. Conventional ultrasonography (US) and real-time US elastography with CAM were performed in 111 women (mean age, 49.4 years; age range, 27-91 years) who had breast lesions (59 benign, 52 malignant). Elasticity images were assigned an elasticity score according to the degree and distribution of strain induced by light compression. The area under the curve and cutoff point, both of which were obtained by using a receiver operating characteristic curve analysis, were used to assess diagnostic performance. Mean scores were examined by using a Student t test. Sensitivity, specificity, and accuracy were compared by using the standard proportion difference test or the Delta-equivalent test. RESULTS: For elasticity score, the mean +/- standard deviation was 4.2 +/- 0.9 for malignant lesions and 2.1 +/- 1.0 for benign lesions (P < .001). When a cutoff point of between 3 and 4 was used, elastography had 86.5% sensitivity, 89.8% specificity, and 88.3% accuracy. When a best cutoff point of between 4 and 5 was used, conventional US had 71.2% sensitivity, 96.6% specificity, and 84.7% accuracy. Elastography had higher sensitivity than conventional US (P < .05). By using equivalence bands for noninferiority or equivalence, it was shown that the specificity of elastography was not inferior to that of conventional US and that the accuracy of elastography was equivalent to that of conventional US. CONCLUSION: For assessing breast lesions, US elastography with the proposed imaging classification, which was simple compared with that of the Breast Imaging Recording and Data System classification, had almost the same diagnostic performance as conventional US.

Adult↗

PubMed2006

Detection of intraductal component around invasive breast cancer using ultrasound: correlation with MRI and histopathological findings.

PURPOSE: The purpose of this study was preoperatively to diagnose the intraductal component, which is indispensable in planning for breast conservation therapy, and also to minimize local recurrence. This study investigated the efficacy of ultrasound (US) in the detection of intraductal component in comparison with magnetic resonance imaging (MRI) and histopathological findings. PATIENTS AND METHODS: In 47 patients with invasive breast cancer, US features of the intraductal component were classified as (a) solid ductal dilatation radiating from the tumor, (b) presence of satellite lesion in the same segment without ductal dilatation, and (c) ductal dilatation between the main tumor and satellite lesion. MRI depicted intraductal extension as the most enhanced area during the first or second phase of the dynamic study. Other criteria for the detection of the intraductal component by MRI were as follows: (a) a satellite lesion around the main tumor, (b) bridging enhancement between the main tumor and satellite lesions. The extent of the intraductal component was measured and classified as mimimal (0-5 mm), moderate (6-15 mm) or wide (>15 mm). RESULTS: In 28 of 47 (60.0%) patients, a wide intraductal component of more than 15 mm was proved histopathologically. Of 28 patients, US and MRI could accurately detect wide intraductal components in 16 patients and 14 patients, respectively. Sensitivity, specificity, and accuracy were 57.1%, 84.2%, and 68.1% respectively for US and 50.0%, 89.5% and 65.9% for MRI, respectively. When both US and MRI results were combined, sensitivity, specificity, and accuracy were 75.0%, 84.2%, and 78.7%. CONCLUSION: Current US examination depicted the intraductal component of breast cancer more accurately than MRI. Further, our study suggests that the use of both US and MRI together is complementary and offers more advantage than US alone.

Adult↗

PubMed2006

Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia.

Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes.

Adenocarcinoma↗

PubMed2006

Alternative lengthening of telomeres in the human adrenocortical carcinoma cell line H295R.

Telomere maintenance can occur in the absence of telomerase by a mechanism referred to as alternative lengthening of telomeres (ALT). ALT is considered to be rare in tumors of epithelial origin. The biological significance and molecular mechanism of ALT have not been well studied in human cancers. It has been reported that clinical samples of adrenocortical carcinoma show a low incidence of telomerase positivity. We characterized an adrenocortical carcinoma cell line, H295R, focusing on the telomere maintenance mechanism, and compared it with telomerase-positive 293 cells and HeLa cells. Telomerase activity could not be detected in H295R cells by the TRAP assay. Among the essential components of the telomerase holoenzyme, only hTERT expression was undetectable by RT-PCR, indicating that the lack of telomerase activity is due to suppression of hTERT. H295R cells had long and heterogeneous telomere DNA, and FISH revealed large nuclear bodies in a few interphase nuclei, which presumably represented ALT-associated PML bodies. These results suggest that H295R cells have the ALT phenotype. Several proteins that are possibly associated with the telomere maintenance mechanism were examined. TRF1 and TRF2 were expressed in H295R cells as well as in 293 cells and HeLa cells. The ratio of hnRNP B1 to A2 was higher in H295R cells than in 293 cells and HeLa cells. In conclusion, the H295R adrenocortical carcinoma cell line is negative for telomerase and maintains its telomeres by the ALT mechanism. We anticipate that H295R cells will be a good model for understanding the significance and mechanism of ALT in human cancers.

Adrenal Cortex Neoplasms↗

PubMed2005

Immunohistochemical study of the hnRNP A2 and B1 in the hippocampal formations of brains with Alzheimer's disease.

To elucidate the post-transcriptional regulation in the subjects with Alzheimer's disease (AD), we employed immunohistochemical techniques and examined the expression of the heterogeneous nuclear ribonucleoprotein (hnRNP) A2 and B1 in the hippocampus with neurofibrillary tangle (NFT) neuropathology. In the mildly affected subjects (Braak stages I and II), the most intense A2 immunoreactivity was observed in the CA3 to CA1 neurons. In the moderately (Braak stages III and IV) and severely affected subjects (Braak stages V and VI), the CA1 region demonstrated a decrease in the number of A2 immunoreactive neurons and in immunoreactivity in the remaining neurons, while within the CA4 to CA2 in the severely affected subjects, the majority of neurons showed increased A2 immunoreactivity. An intense B1 immunoreactivity was observed throughout the CA subfields. In the CA1 subfield of the moderately affected subjects and in the extensive hippocampal regions of the severely affected subjects, a decrease in B1 immunoreactivity was observed. Double-immunolabeling studies demonstrated that tangle-bearing neurons reduced A2 and B1 immunoreactivity. Our study suggests that hnRNP A2 and B1 display different responses in the AD hippocampus, and further suggests that the post-transcriptional regulation is disturbed in neurons of the AD hippocampus.

Aged↗

PubMed2005

Histiocytoid breast carcinoma: solid variant of invasive lobular carcinoma with decreased expression of both E-cadherin and CD44 epithelial variant.

Histiocytoid breast carcinoma (HBC) is a rare type of breast carcinoma with morphologic characteristics resembling those of histiocytes. Described herein are cytological and histological findings in a case of HBC. Fine-needle aspiration cytology revealed numerous loosely cohesive tumor cells with abundant foamy to granular cytoplasm and bland-appearing nuclei. The resected tumor exhibited a solid growth pattern instead of classic invasive lobular patterns observed in most reported cases of HBC. However, distinct intracytoplasmic lumina and Pagetoid extension to ducts suggested that this tumor was a variant of invasive lobular carcinoma. To determine the cause of the loose cellular cohesiveness of this HBC, its expression of the epithelium-related cell adhesion molecules E-cadherin and CD44v8-10 (CD44 epithelial variant) was examined. Immunohistochemically, E-cadherin was not detected, similar to most lobular carcinomas. Furthermore, competitive reverse transcription-polymerase chain reaction (RT-PCR) analyses among alternatively spliced variants of CD44 revealed that the ratio of expression of CD44v8-10 to that of CD44v10 (dominant variant in leukocytes) was lower than that for the reference breast carcinoma samples. It is concluded that the present case of HBC was a solid variant of invasive lobular carcinoma exhibiting foamy to granular cytoplasmic change. Decreased expression of both E-cadherin and CD44 epithelial variant may be responsible for the loose cellular cohesiveness observed in HBC.

Aged↗

PubMed2005

Altered expression patterns of heterogeneous nuclear ribonucleoproteins A2 and B1 in the adrenal cortex.

Several proteins implicated in hormonogenesis of the adrenal cortex have alternatively spliced isoforms, which respond differently to adrenocorticotropic hormone (ACTH). Heterogeneous nuclear ribonucleoproteins A2 and B1 are among the abundant pre-mRNA-binding proteins involved in alternative splicing. We examined the expression of A2 and B1 in normal adrenal cortex and tumors. B1 was variably expressed in the zona fasciculata-reticularis, although A2 was diffusely expressed in the three zones. B1 was more abundant in compact cells than clear cells, and B1 expression was frequent in the zona reticularis, which consists mainly of compact cells. In three kinds of cortical adenomas autonomously producing hormones, B1 was generally overexpressed and there were no significant differences among them. In cortisol-producing tumors, non-tumor parts of the cortex, which were generally atrophic due to low ACTH, had less B1 protein than normal adrenals. These results suggested a correlation between B1 expression and the hormonal activity responding to ACTH. In vitro ACTH stimulation induced a biphasic expression of B1 in an H295R cortical carcinoma cell line, and it paralleled hormonogenesis. Conclusively, B1 expression varied in relation to the hormonal activity responding to the ACTH, and it may provide a key to elucidating the splicing mechanisms involved in hormonogenesis.

Adrenal Cortex↗

PubMed2005

Expression of heterogeneous nuclear ribonucleoproteins A2 and b1 in the thyroid follicular cells.

Several proteins implicated in hormonogenesis of the thyroid have alternatively spliced isoforms. Alternative splicing of pre-mRNA is considered to be important to regulate the hormonal activity. Heterogeneous nuclear ribonucleoproteins (hnRNP) A2 and B1 are two of the abundant nuclear RNA-binding proteins involved in alternative splicing. We examined the expression of hnRNP A2 and B1 in the thyroid, paying particular attention to the relationship between their function and the cellular morphology. B1 was expressed more frequently in cuboidal follicular cells that are hormonally active than in flat follicular cells in normal thyroid, although A2 expression showed no significant difference in two cell types. In Graves' disease, the patients who had high serum levels of triiodothyronine and thyroxine showed significantly increased expression of B1. B1 expression did not differ significantly between normal thyroids and thyroid neoplasms, except undifferentiated (anaplastic) carcinoma. Conclusively, B1 expression varied in relation to hormonal activity in thyroid follicular cells. B1 protein is a good immunohistological marker to detect hormonal activity of follicular cells, and may provide a key to elucidate the splicing mechanisms involved in thyroid hormonogenesis.

Alternative Splicing↗

PubMed2004

Immunohistochemical study of hnRNP B1 in the postmortem temporal cortices of patients with Alzheimer's disease.

In order to examine the post-transcriptional regulations in Alzheimer's disease, we employed immunohistochemical techniques and examined the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) B1 in the inferior temporal cortex of subjects with Alzheimer's disease. In the mild cases, intense B1 immunoreactivity was observed in neurons of layer V, and less intense immunoreactivity was observed in layers II and III. The overall distributions and intensities of B1 immunoreactivity were undistinguishable among mild, moderate, and severe cases. Double-immunolabeling with MC1 and B1 demonstrated that B1 immunoreactivity was preserved in the majority of neurofibrillary tangle (NFT)-bearing neurons. Our study suggests that hnRNP B1-associated post-transcriptional regulations are preserved in the inferior temporal cortex of Alzheimer's disease.

Aged↗

PubMed2004

Expression of the human telomerase reverse transcriptase in pheochromocytoma and neuroblastoma tissues.

In an effort to clarify the role of telomerase in the pathogenesis of pheochromocytomas and neuroblastomas, and to test whether its component could serve as a marker of malignancy, we measured telomerase reverse transcriptase (TERT) mRNA in 31 human pheochromocytoma tissue samples (5 malignant, 23 benign and 3 suspected malignant) and 16 neuroblastoma tissues (9 unfavorable and 7 favorable). All cases were classified by both the clinical course and histopathological examination. Malignancy was defined as the presence of metastasis and/or extensive local invasion. TERT mRNA was determined by nested PCR and a real-time PCR system (LightCycler). By nested PCR methods, 5 of the 5 malignant pheochromocytoma samples were positive (sensitivity = 100%), and 21 of 23 benign pheochromocytoma samples were negative (specificity = 91%) in pheochromocytomas. Four out of five malignant tumors were positive for either hTERT expression or Ki-67/MIB-1 immunoreactivity. In the neuroblastoma tissues, 9 of the 9 unfavorable samples were positive (sensitivity = 100%), and only 2 of 7 favorable samples were negative (specificity = 29%). We also determined the expression of the hTERT mRNA by real-time PCR to quantitate the mRNA. The mean values of hTERT mRNA by real time PCR in benign and malignant pheochromocytomas were 2 and 26 arbitrary units (AU), respectively. The difference was not significant by the U-test. The mean values of hTERT mRNA in favorable and unfavorable neuroblastoma were 203 and 497 AU, respectively. This difference was also not significant (U-test). N-Myc mRNA expression correlated with the expression of hTERT mRNA in the neuroblastoma samples (r = 0.534, p = 0.0317). Thus, hTERT mRNA might be a potential marker for estimating the malignancy of pheochromocytomas and neuroblastomas.

Adolescent↗

PubMed2004

Expression and alternative splicing pattern of human telomerase reverse transcriptase in human lung cancer cells.

Telomerase activity is generally considered to be necessary for cancer cells to avoid senescence. The expression of human telomerase reverse transcriptase (hTERT) is believed to be a rate-limiting step in telomerase activation. Recently, it has been proposed that the alternative splicing of hTERT is also involved in regulation of telomerase activity. However, the regulatory mechanism of telomerase in cancer cells has not been thoroughly investigated. To clarify it in lung cancer cells, we measured the expression of the hTERT transcript, analyzed its alternative splicing by RT-PCR, and compared it with telomerase activity and telomere length. The expression of the hTERT transcript was positively correlated with telomerase activity in lung cancer cells. Cancer cells with high telomerase activity contained 4 splicing variants of hTERT, and the full-length variant was 31.3-54.2% of the total transcripts. Cells of the TKB-20 cell line, which has extremely low telomerase activity, showed a different splicing pattern of hTERT in addition to low expression. The functional full-length variant was scarcely detected in TKB-20 cells, suggesting that the telomerase activity was repressed by alternative splicing of hTERT. Telomere length was not necessarily correlated with telomerase activity or hTERT expression in lung cancer cells. Cells of the TKB-4 cell line that also showed relatively low telomerase activity (as TKB-20 cells) had long telomeres. In conclusion, hTERT expression is regulated at both the transcriptional and post-transcriptional levels in lung cancer cells, and the alternative splicing of hTERT is involved in the control of telomerase activity.

Alternative Splicing↗

PubMed2004

Expression of hnRNP A2/B1 proteins in small airway epithelial cells.

The overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, especially of B1 has been reported informative to detect pre-clinical lung cancer for early detection. However, relatively little work has been performed on the expression of hnRNP A2/B1 in non-malignant airway cells; such information is clearly required to investigate whether overexpression of this protein could be a specific marker for early lung cancer detection. In order to evaluate whether the expression of hnRNP A2/B1 is specific for cancer cells, we investigated the expression of the protein in human small airway epithelial (HSAE) cells. Using immunostaining and Western blotting with monoclonal antibodies, 4G8 (specifically reacts A2) and 2B2 (specific to B1), expression of hnRNP A2/B1 in HSAE cells was evaluated. Northern blotting and quantitative RT-PCR were also performed. In HSAE cells, hnRNP A2 as well as B1 were expressed primarily in the nucleus excluding the nucleolus, although the expression of A2 protein was weaker than that of B1 protein. Staining pattern of hnRNP A2/B1 in HSAE cells was similar to that observed in control cancer cells. Western blotting with 4G8 and 2B2 apparently demonstrated expression of A2 and B1 in HSAE cells. In Northern blotting, both hnRNP A2 mRNA and B1 mRNA were observed in HSAE cells as shown in control cancer cells. hnRNP A2/B1 was apparently expressed in HSAE cells, although the expression in HSAE cells was weaker than that of cancer cells. More quantitative determination of A2/B1 is required to elucidate their significance in early lung cancer detection.

Blotting, Northern↗

PubMed2003

Alterations of heterogeneous nuclear RNP A2 and B1 in the hippocampus of the rat after perforant pathway lesion.

We examined alterations in post-transcriptional regulation following deafferentation of the perforant pathway by focusing on heterogeneous nuclear ribonucleoprotein (hnRNP) A2 and B1 in rat hippocampi subjected to perforant pathway lesions. In control brains, immunoreactivity to both was observed in the nuclei of neurons throughout the hippocampus using immunohistochemical techniques. From 1 to 14 days post-lesion, a slight increase in A2 immunoreactivity was observed in neurons within the dentate granular layer as well in the pyramidal cells of the cornus Ammon fields ipsilateral to the lesion. In contrast, we observed a marked decrease in B1 immunoreactivity in the same regions at 1, 3 and 7 days post-lesion. All these alterations, however, were transient. A2 immunoreactivity returned to normal levels by 30 days post-lesion, and B1 immunoreactivity had completely recovered by 14 days post-lesion. The results of immunoblot analysis for A2 and B1 were wholly consistent with immunohistochemical observations. Our study suggests that post-transcriptional regulation in the hippocampal neurons changes after a perforant pathway lesion. Our study further suggests that the functions of hnRNPA2 and B1 are different, as each was differentially involved in the plastic response to deafferentation of the perforant pathway.

Acetylesterase↗

PubMed2003

Cytokeratin 19 fragment in patients with nonmalignant respiratory diseases.

STUDY OBJECTIVE: Cytokeratin 19 fragment (CYFRA) is a specific tumor marker in patients with lung cancer; however, it has been reported that serum CYFRA levels are elevated in some patients with nonmalignant respiratory diseases such as interstitial pulmonary fibrosis (IPF) and collagen disease-associated pulmonary fibrosis (CDPF). To investigate the serum CYFRA levels in nonmalignant respiratory diseases in detail, we studied 413 patients with respiratory diseases. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Four hundred thirteen patients with nonmalignant respiratory diseases and lung cancer. MEASUREMENTS AND RESULTS: Serum CYFRA levels were measured with a commercially available enzyme immunoassay kit. Immunohistochemical study was performed using monoclonal antibody Ks 19.1 (Rosch Diagnosica; Bern, Switzerland) on surgically resected or autopsied lung specimens. Gel electrophoresis and immunoblotting was performed with serum samples. In 149 patients with nonmalignant diseases except IPF and CDPF, the ratio of patients with > 3.5 ng/mL of serum CYFRA was 13.4%. In 13 of 30 patients (43.3%) with IPF and CDPF, the serum CYFRA levels were abnormally elevated. The 95th percentile serum CYFRA level of the patients with nonmalignant respiratory diseases was 6.2 ng/mL, and none of them had CYFRA levels > 20.3 ng/mL. Survival in patients with IPF and CDPF with elevated serum CYFRA levels were significantly lower than in those with normal range (p = 0.0335). Western blotting using serum from nonmalignant lung diseases and patients with lung cancer showed no apparent difference between them. An immunohistochemical study indicated CYFRA was selectively expressed in the pulmonary epithelial cells that covered the remodeling alveolar septi in nonmalignant respiratory disease. CONCLUSION: Serum CYFRA was elevated in some nonmalignant respiratory diseases, especially in IPF and CDPF. The value of serum CYFRA would reflect the severity of lung injury in nonmalignant respiratory diseases and might be related to the prognosis in patients with IPF and CDPF.

Adult↗

PubMed2003

Reduced expression of heterogeneous nuclear ribonucleoprotein B1 in adult T-cell lymphoma/leukemia.

It is considered that hnRNP B1 expresses similarly in the various types of tumor cells. Recently, we demonstrated high B1 expression in B-cell lymphoma and carcinoma. To evaluate the difference of B1 expression between B and T-cell lymphoma, we immunologically studied the B1 expression in 22 cases with nodal T-cell lymphoma, comprising adult T-cell leukemia/lymphoma (ATLL; n=15) and angioimmunoblastic T-cell lymphoma (AILD; n=7), using an anti-hnRNP B1 monoclonal antibody, 2B2. In ATLL cases, scattered large transformed lymphoma cells demonstrated strong B1 expression, while the medium-sized lymphoma cells were negative. On the one hand, lymphoma cells in AILD diffusely expressed B1. The mean B1 expression rate in ATLL was 22%, which was significantly lower than that in AILDs (45%), B-cell lymphomas (44%), and metastatic carcinomas (53%) (p<0.01). Our result might suggest that process of hnRNP B1 expression in ATLL differs from those in other lymphoid neoplasms and carcinoma.

Adolescent↗

PubMed2003

Establishment and characterization of novel xenograft models of human biliary tract carcinomas.

In order to develop new therapeutic regimens for biliary tract cancers, which carry dismal prognoses, the establishment of a human biliary tract cancer xenograft model is essential. Herein, we report the successful establishment and characterization of two xenograft models of human biliary tract cancers. An adenosquamous gallbladder cancer cell line (TGBC-44) and a bile duct adenocarcinoma cell line (TGBC-47) were obtained from fresh surgical specimens in our department and subcutaneously inoculated into nude mice. The overall tumor take rate was 100% and solid tumors grew measurable after 5 and 7 days for TGBC-44 and TGBC-47, respectively. Tumor doubling time was 3.9+/-1.1 and 4.1+/-0.5 days in the exponential growth phase in TGBC-44 and TGBC-47 xenografts, respectively. Isozyme test and karyotype analysis confirmed the human origin. Histopathology analysis revealed that the TGBC-44 xenograft retained both the squamous and the adenocarcinoma components, and the TGBC-47 xenograft exhibited poorly differentiated adenocarcinoma as in the corresponding original tumors. Immunohistochemistry and Western blotting studies revealed positive and similar expression of platelet derived endothelial growth factor/thymidine phosphorylase (PDGF/TP), thymidylate synthase (TS), and cyclooxygenase-2 (COX-2) in both original tumors and xenograft models. No macroscopic metastases were found at the time of sacrifice. We have successfully established two models of human biliary tract cancer, gallbladder and bile duct cancer. Models retained the morphological and biochemical characteristics of the original tumor and demonstrated constant biological behavior in all transplanted mice. These models could be useful tools for developing new diagnostic and therapeutic strategies against biliary tract cancers.

Animals↗

PubMed2002

Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma.

Small cell lung cancer (SCLC) and neuroblastoma (NB), the most aggressive adult and infant neuroendocrine cancers, respectively, are immunologically characterized by a severe reduction in major histocompatibility complex (MHC) that is indispensable for anti-tumor immunity. We had reported that the severe reduction of MHC in SCLC was caused by a deficient interferon (IFN)-gamma-inducible expression of class II transactivator (CIITA) that is known as a very important transcription factor for IFN-gamma-inducible class II and class I MHC expression (Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, Fujimoto M, Yokohama K, Ogata T: Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 1999, 187:191-199). Here, we demonstrate that the reduction of MHC in NB was also caused by a deficient IFN-gamma-inducible expression of CIITA and that the deficiency in SCLC and NB was caused by similar mechanisms. Human achaete-scute complex homologue (HASH)-1, L-myc, and N-myc, which are specifically overexpressed in SCLC and NB, bound to the E-box in CIITA promoter IV and reduced the transcriptional activity. Anti-sense oligonucleotide experiments revealed that overexpressed L-myc and N-myc lie upstream in the regulatory pathway of HASH-1 expression. The expression of HASH-1 was also up-regulated by IFN-gamma. Our results suggest that SCLC and NB have complicated mechanisms of IFN-gamma-inducible CIITA transcription deficiency through the overexpressed HASH-1, L-myc, and N-myc. These complicated mechanisms may play an important role in the escape from anti-tumor immunity.

Basic Helix-Loop-Helix Proteins↗

PubMed2002

Overexpression of heterogeneous nuclear ribonucleoprotein B1 in lymphoproliferative disorders: high expression in cells of follicular center origin.

It is reported that overexpression of hnRNP A2 and B1 proteins is useful for detecting early cancers, and that B1, a splicing minor isoform of A2, is more specific than A2. The B1 expression is still undetermined in human lymphoid tissues. We quantitatively studied the B1 expression in 85 lymph node specimens, comprising reactive lymphoid hyperplasia (RLH; n=8), B-cell lymphoma (n=23), T-cell lymphoma (n=22), and metastatic carcinoma (n=32). Immunostaining and immunoblotting analyses with an anti-B1 monoclonal antibody, 2B2 were performed, and the two sets of results correlated with each other (p<0.05). In RLH specimens, B1 expression rate was significantly higher in follicular centers (FC; 44%) than in mantle zone (MZ; 15%) and paracortex (16%) (p<0.01). B1 expression was statistically higher in B-cell lymphoma than in T-cell lymphoma (p<0.01). In B-cell lymphomas, B1 expression rates were 51% in diffuse large B-cell lymphoma (DLBL; n=5) and 45% in follicular lymphoma (FL; n=16), and they were almost the same as that of the FC. Especially in DLBLs, CD10+ FC-origin lymphomas expressed greater amount of B1 than CD10- non-FC-origin lymphomas. B1 expression rate was low in mantle cell lymphoma (MCL; n=2) and similar to that of MZ in RLH. These results suggest that B1 expression is associated with differentiation in lymphoid tissue rather than transformation. B1 expression increases during the process of B-cell differentiation in the FC, and that high B1 expression is maintained in B-cell lymphomagenesis, especially in cells of FC-origin DLBL.

Adolescent↗