BRAF and KRAS mutations in stomach cancer.

Ras proteins control signaling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. BRAF, which encodes a RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers. The activating mutation of BRAF is known to play a role in tumor development.

Induction of phenylalanine ammonia-lyase gene expression by paraquat and stress-related hormones in Rehmannia glutinosa.

Rehmannia glutinosa is a medicinal herb that is tolerant to the non-selective herbicide paraquat. Acteoside, a phenolic compound present in the plant, has been shown to inhibit paraquat. To understand regulation of the phenylpropanoid pathway that produces the acteoside moiety, we isolated a phenylalanine ammonia-lyase (PAL) cDNA clone (RgPAL1) and used it to examine PAL expression.

Inactivating mutations of CASPASE-7 gene in human cancers.

Caspase-7 is a caspase involved in the execution phase of apoptosis. To explore the possibility that the genetic alterations of CASPASE-7 might be involved in the development of human cancers, we analysed the entire coding region and all splice sites of human CASPASE-7 gene for the detection of somatic mutations in a series of human solid cancers, including carcinomas from stomach, colon, head/neck, esophagus, urinary bladder and lung. Overall, we detected CASPASE-7 mutations in two of 98 colon carcinomas (2.

Mutational analysis of Noxa gene in human cancers.

There has been mounting evidence that dysregulation of apoptosis is involved in the mechanisms of cancer development and somatic mutations of apoptosis-related genes have been reported in human cancers. Noxa, a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family, is known to interact with anti-apoptotic Bcl-2 family members and induces apoptosis. The aim of this study was to explore the possibility that the Noxa gene is mutated in human cancers.

Mutational analysis of salvador gene in human carcinomas.

It is believed that clonal expansion and cancer growth is the result of the deregulation of proliferation and cell death. Recently, salvador, a molecule that can regulate both cell proliferation and cell death, was identified. It was also reported that human salvador (hWW45) is mutated in some cancer cell lines.

Inactivating mutations of caspase-8 gene in colorectal carcinomas.

Background & Aims: There has been evidence that dysregulation of apoptosis is involved in the pathogenesis of cancer development. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis. The aim of this study was to explore the possibility that mutation of the caspase-8 gene might be involved in the development of colorectal cancer.

A single nucleotide polymorphism in the E-cadherin gene promoter-160 is not associated with risk of Korean gastric cancer.

Recently, the -160 C/A polymorphism, located within the regulatory region of Ecadherin promoter, has been shown to influence E-cadherin transcription by altering transcription factor binding. We examined the effect of this polymorphism on risk of gastric cancer and on histological classification of intestinal- and diffuse-type gastric cancer in 146 normal healthy individuals and 292 Korean gastric cancer patients. Genomic DNA samples were examined by polymerase chain reaction (PCR)-single strand conformational polymorphism (SSCP)-sequencing and confirmed by restriction fragment length polymorphism (RFLP).

Phase II Study of Gemcitabine and Vinorelbine as Second-Line Chemotherapy in Non-Small Cell Lung Cancer.

Purpose: With the increased use of chemotherapy for non small cell lung cancer (NSCLC), a growing group of patients can now be considered for second-line chemotherapy. However, guidelines for the second line treatment remain to be developed. The objective of this study was to evaluate the efficacy and safety of the gemcitabine and vinorelbine combination therapy in patients with advanced NSCLC, pretreated with taxane and platinum based regimens.

Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer.

The serine protease Omi/HtrA2 is released from mitochondria into the cytosol after apoptosis stimuli, inducing apoptosis in a caspase-independent manner through its protease activity and in a caspase-dependent manner by neutralizing the inhibition of inhibitor of apoptosis proteins (IAPs) on caspases. Alteration of apoptosis is essential for cancer development, and cancer cell death by radiation and chemotherapy is largely dependent upon apoptosis. Thus, analysis of the expression status of Omi/HtrA2, a regulator of apoptosis, in cancer tissues is needed for an understanding of cancer development.

Overexpression of S100A4 is closely related to the aggressiveness of gastric cancer.

Elevated levels of the calcium-binding protein S100A4 cause metastasis of benign rat mammary tumor cells. To investigate whether S100A4 plays an important role in the invasion and metastasis of gastric cancers, we examined the gene mutations in the coding regions and expression patterns of the S100A4 in gastric adenocarcinoma in Korea. Moderate to strong expression of S100A4 was found in 53 (68.

Immunohistochemical expression of integrins and extracellular matrix proteins in non-small cell lung cancer: correlation with lymph node metastasis.

Purpose: For patients with non-small cell lung cancer (NSCLC), the biggest threat to survival is metastasis. During metastatic cascade, tumor cells interact with extracellular matrix (ECM) through certain adhesion molecules such as integrins. The aim of this study was to analyze the distribution of the main integrins and ECM in a series of patients with NSCLC to assess their distribution and correlate with lymph node (LN) metastasis of NSCLC.

Mutational analysis of Fas ligand gene in human non-Hodgkin lymphoma.

Among the systems triggering apoptosis, the Fas-Fas ligand (FasL) system is recognized as a major pathway for the induction of apoptosis in cells and tissues. Ligation of Fas by either an agonistic antibody or FasL transmits a 'death signal' to the target cell, potentially triggering apoptosis. Alterations of genes along the Fas-mediated apoptosis pathway have been reported in many human cancers.

Genetic alterations of the HCCS1 gene in Korean hepatocellular carcinoma.

We analyzed the gene mutations and loss of heterozygosity (LOH) of the HCCS1 gene using intragenic polymorphic markers in a series of 88 primary HCCs. We found two sequence variations at exon 5 and 14 in both normal and tumor DNAs of case 50 and 51, respectively. The variation in case 50 led to a reading frameshift and a premature stop (TGA) at codon 125 and case 51 showed amino acid change at codon 448 (Val-->Ala, GTG-->GCG).

Paclitaxel and Cisplatin Combination Chemotherapy in Pretreated Breast Cancer.

Purpose: A single institute trial of combination chemotherapy, with paclitaxel and cisplatin, in patients with metastatic breast cancer, having failed previous combination chemotherapy, was performed.

Materials And Methods: Patients were only eligible for this study if there disease had progressed, following treatment with previous chemotherapy, in either an adjuvant or a metastatic setting. Paclitaxel 175 mg/m2 was administered as a 3-hour continuous infusion on day 1, and cisplatin 80 mg/m2 was administered for 2 hours on day 2, with adequate hydration.

Immunohistochemical analysis of Smac/DIABLO expression in human carcinomas and sarcomas.

Second mitochondria-derived activator of caspases (Smac/DIABLO) is released from mitochondria into the cytosol during apoptosis, promoting caspase activation by neutralizing the inhibition of inhibitor of apoptosis proteins (IAPs) on caspases. Alteration of apoptosis is essential for cancer development, and cancer cell death by radiation and chemotherapy is largely dependent upon apoptosis. In this study, archival tissues of 100 carcinomas and 50 sarcomas from various origins were analyzed by immunohistochemistry for the expression of Smac/DIABLO.

Increased expression of FLIP, an inhibitor of Fas-mediated apoptosis, in stomach cancer.

Despite the cell surface expression of Fas (Apo-1/CD95), many types of tumor cells, including stomach cancer cells, are resistant to Fas-mediated apoptosis, indicating the presence of inactivating mechanisms of Fas signaling. Expression of FLICE-like inhibitory protein (FLIP), one of the inhibitory proteins of Fas-mediated apoptosis, has been reported in several cancer types, but not in stomach cancer. In the present study, we analyzed the expression of Fas and FLIP in 60 advanced gastric adenocarcinomas by immunohistochemistry using a tissue microarray approach.

Double primary mucoepidermoid carcinoma and hepatocellular carcinoma of the liver--a case report.

Double primary mucoepidermoid-hepatocellular carcinoma of the liver is extremely rare, and only one case has previously been reported in the literature, although there have been about 14 cases of primary mucoepidermoid carcinoma of the liver. Most of the reported hepatic mucoepidermoid carcinoma showed a poor prognosis. We presently report the second case of a double primary mucoepidermoid carcinoma and hepatocellular carcinoma with a brief review of the published literature.

Stomach cancer highly expresses both initiator and effector caspases; an immunohistochemical study.

Caspases play an essential role during apoptotic cell death. While caspases 8 and 10 act as initiator caspases of the extrinsic apoptosis pathway, caspase 9 acts as an initiator caspase of the intrinsic apoptosis pathway. Caspase 3 is considered to be the main effector caspase involved in both intrinsic and extrinsic pathways.

Nod1, a CARD protein, enhances pro-interleukin-1beta processing through the interaction with pro-caspase-1.

The production of bioactive interleukin-1beta (IL-1beta), a pro-inflammatory cytokine, is mediated by activated caspase-1. One of the known molecular mechanisms underlying pro-caspase-1 processing and activation involves interaction between the caspase recruit domains (CARDs) of caspase-1 and a serine/threonine kinase RIP2. While the association of Nod1 with both caspase-1 and RIP2 is already known, the consequences of these interactions are poorly understood.

Non-small cell lung cancers frequently express phosphorylated Akt; an immunohistochemical study.

Mounting evidence suggests that the alterations of Akt/protein kinase B (PKB) play an important role in tumorigenesis. Phosphorylated Akt regulates many of the key effector molecules involved in apoptosis, angiogenesis, and cell cycle progression during tumorigenesis. The expression of phosphorylated Akt has been described in some human malignancies, but not in primary human lung cancer.

Expression of HGF/SF and Met protein is associated with genetic alterations of VHL gene in primary renal cell carcinomas.

We analyzed the genetic alterations of VHL, HGF/SF, and Met genes and the expression pattern of HGF/SF and Met protein in 26 renal cell carcinomas (RCCs). We found five mutations of the VHL gene and frequent LOH (50%) only in non-papillary clear cell RCC. We found six cases in which the CpG island of VHL was methylated.

Changes of Telomerase Activity and Proliferation by Inhibition of Reverse Transcriptase Activity in Human Cancer Cell.

Purpose: Activation of telomerase is proposed to be an essential step in cancer cell immortalization and cancer progression. 3'-azido-2',3'-dideoxythymidine (AZT), a reverse transcriptase inhibitor, was reported to be incorporated in telomeric sequences of immortalized cells in culture and to suppress the activity of telomerase and the cell proliferation. In this study, after induction of cancer cell senescence with long-term treatment of AZT, we investigated the dynamics of telomerase subunits (hTERT, hTR, TEP), transcription factors (c-Myc, Mad1), telomerase activity, and finally, telomere length in a human breast cancer cell line.

Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer.

Many types of cancer cells are resistant to Fas-mediated apoptosis by several mechanisms, including the mutations of the genes involved in Fas-mediated apoptosis. In this study, to explore the possibility that the mutations of the genes involved in the proximal pathway of Fas-mediated apoptosis (Fas, FADD, caspase 8 and caspase 10) are involved in cancer metastasis, we have analysed somatic mutation and deletion of these genes in 80 non-small cell lung cancers (NSCLCs) with (n=43) and without (n=37) metastasis to the regional lymph nodes. We found 12 mutations (four Fas, four FADD, and four caspase 10 mutations) in 11 of 80 NSCLCs (13.

Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas.

Caspase 10 (Mch4/FLICE2) is a caspase homologous to caspase 8. A recent report described that inherited CASP10 gene mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome (ALPS). In this study, to explore the possibility that mutation of this gene might be involved in the development of non-Hodgkin lymphoma (NHL), we have analyzed the entire coding region and all splice sites of the CASP10 gene for the detection of somatic mutations in 117 human NHLs.

Inactivating mutations of the caspase-10 gene in gastric cancer.

We have analysed the genetic alteration of the entire coding region and all splice sites of caspase-8 and -10 genes in 99 gastric cancers by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. We found LOH of the caspase-8 and -10 in nine (28%) of 32 and in four (15%) of 26 informative cases, respectively. Overall, three of 99 gastric cancers (3%) were found to have the caspase-10 mutations, which were identified in the coding regions of the death effector domain (codon 147) and the p17 large protease domain (codons 257 and 410), whereas no mutation was detected in caspase-8.