This study aimed to evaluate whether the elevated level of hypoxia-inducible factor-1 (HIF-1 ) correlated with histologic types, angiogenesis, tumor cell proliferation, and clinical parameters in common non-small cell lung carcinomas (NSCLCs). We performed immunohistochemical stains using paraffin-embedded tissue blocks from 84 cases of operable NSCLC [No. of squamous cell carcinoma (SCC), 45; No. of adenocarcinoma (AC), 39]. HIF-1 expression was related with histologic types (66.7% in SCCs vs 20.5% in ACs, p<0.001), but not with lymph node status, tumor stage, vascular endothelial growth factor expression, microvessel density (MVD), and proliferating cell nuclear antigen (PCNA) index (p>0.05, respectively). As for the histologic types, MVD and PCNA index were significantly higher in SCCs than in ACs (p=0.009 and p=0.016, respectively). Among HIF-1 positive carcinomas, MVD was significantly higher in HIF-1 positive SCCs than in HIF-1 positive ACs (p= 0.023). The overall survival curves were not associated with HIF-1 expression or any other histologic parameters (p>0.05). These findings suggest that HIF-1 expression in NSCLCs may play a differential role according to histologic types, but its prognostic significance is indeterminate.
Background : The multidrug resistance (mdr1), multidrug resistance associated protein (mrp1), and glutathione-s-transferase (gst) genes have been associated with treatment failure in acute myeloid leukemia (AML). c-jun N-terminal kinase (JNK) activity is increased in response to chemotherapeutic agent.Methods : To investigate the significance of multidrug resistance (mdr) parameters and JNK activity, bone marrow or peripheral blood cells from 52 patients with AML were analyzed. RT-PCR was performed for mdr1, mrp1, and gst gene expression. JNK expression and activity were measured using an immunoe-nzymatic kinase assay and a western blot method.Results : High level expression of mdr1, mrp1, and gst mRNA was observed in 38.5%, 48.1% and 54.3% of AML cases, respectively. The remission rate was significantly low in cases with an older age (>55 yr), a high WBC count, poor chromosomal abnormalities, a high level expression of mdr1 and mrp1. The WBC count and mdr1 mRNA expression were independent predictors for the outcome to induction chemotherapy. There was a shorter duration of overall survival in the patients with an older age, a high WBC count, chromosome aberrations, high level expressions of mdr1 and mrp1 mRNA, and JNK activation. The patient's age, WBC count and chromosomal abnormalities were independent predictors for overall survivals. The majority (28/30) of AML cases did not show any levels of JNK activation except for two cases, which were associated with an extremely high WBC count, chromosomal aberration, high level expressions of mdr1, mrp1 and gst mRNA, and treatment resistance.Conclusions : These data indicate the influences of mdr1 and mrp1 mRNA expression on the clinical outcome of AML to induction chemotherapy. But it will be necessary to investigate further whether blast cells of AML resistant to chemotherapy retain the capacity to activate JNK, and relate to MDR parameters. (Korean J Lab Med 2007;27:229-36)
Abstract. The tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirusmediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the cotreatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells. IntroductionTNF-related apoptosis-inducing ligand (TRAIL), which belongs to the family of TNF, induces apoptosis in a wide variety of tumor cells in vitro and in vivo but does not cause toxicity in a majority of normal cells (1,2). Thus, TRAIL has been suggested as a novel anti-cancer therapeutic drug. The TRAIL-mediated apoptotic signal is transduced through the cell surface death receptor (DR)s such as DR4/TRAIL-R1 and DR5/TRAIL-R2 (3,4). Detailed studies have shown that TRAIL triggers apoptosis by recruiting the initiator procaspase-8 through the adaptor protein FADD. Caspase-8 can directly activate downstream effector caspases including procaspase-3, -6 and -7, or cleave Bid, which triggers mitochondrial damage (5,6). However, different types of cancer cells appear to differ in their sensitivity to TRAIL treatment. Recent studies have reported that prostate and renal cancer cells are resistant to TRAIL treatment due to an up-regulation of Akt activity and enhanced FLIP expression (7,8). In addition, it has been reported that the resistance of certain gastric cancer cells to TRAIL-induced apoptosis can be explained by the up-regulation of FLIPs by Akt, indicating that Akt is a crucial component in the regulation of TRAIL-induced apoptosis (9). In contrast, other studies failed to demonstrate a link between FLIP expression and TRAIL resistance using melanoma and Burkitt's lymphoma (10,11).The human reovirus is a ubiquitous, non-enveloped virus with 10 segments of double-stranded RNA (12). The virus infection is usually restricted to the upper respiratory and gastrointestinal tracts and is often...
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