High Survivin and Low Zinc Finger of the Cerebellum 1 Expression Indicates Poor Prognosis in Triple-negative Breast Carcinoma.

PURPOSE: Triple-negative breast carcinoma (TNBC) is accompanied with high risk of metastasis and recurrence. The present study aimed to explore the clinicopathological and prognostic roles of putative tumor-related genes in patients with TNBC. METHODS: Thirty pairs of frozen-thawed tumors were used to select reliable indicators via real-time quantitative polymerase chain reaction (RT-qPCR). Then, 150 pathology specimens were used to evaluate the expression of proteins in TNBC through immunohistochemistry. In addition, Kaplan-Meier curves and Cox regression analysis were also performed to analyze the overall survival and disease-free survival. RESULTS: RT-qPCR results indicated that among all the proteins analyzed using fresh-frozen TNBC samples, the expression levels of only Survivin and zinc finger of the cerebellum 1 (ZIC1) were obviously different from those in the corresponding normal tissues. Survivin and ZIC1 expression had opposite effects on the clinicopathological diagnosis and prognostic assessment in TNBC patients. Further, there was a negative correlation between Survivin and ZIC1 expression. In addition, the "Survivin-positive ZIC1-negative group" was associated with histologic grade, lymph node metastasis, and TNM staging (p < 0.001) and this was also an independent factor for evaluating the prognosis of TNBC in patients. CONCLUSION: In summary, the expression levels of Survivin and ZIC1 in TNBC are different from those in normal tissues and are negatively correlated mutually. The combined detection of Survivin and ZIC1 expression levels could allow better comprehensive diagnosis and prognostic evaluation for TNBC patients.

High Oct4 predicted worse prognosis of right-sided colon cancer patients.

AIM: This present study was aimed to compare the role of Oct4 in left-sided colon cancer (LCC) with right-sided colon cancer (RCC). PATIENTS & METHODS: One hundred and fifty one pathology specimens, 68 frozen-thawed tumors and cell lines were used to evaluate the role of Oct4 in LCC and RCC through immunohistochemistry, western blot and real-time quantitative PCR. RESULTS: In LCC, positive expression of Oct4 was positively related to differentiation and Dukes stage (p < 0.01). Only in RCC, Oct4 expression was also positively related to lymphatic invasion and survival rates of 'negative group' were significantly higher. CONCLUSION: In summary, Oct4 was related to tumor differentiation and later Dukes stage in colon cancer, and was correlated with invasion of lymphatic only in RCC. In addition, Oct4 was a potential prognostic indicator in RCC.

Interruption of hepatocyte growth factor signaling augmented oridonin-induced death in human non-small cell lung cancer A549 cells via c-met-nuclear factor-κB-cyclooxygenase-2 and c-Met-Bcl-2-caspase-3 pathways.

The aim of this study was to elucidate the molecular mechanisms mediating hepatocyte growth factor (HGF)-induced protection against oridonin-induced apoptosis in A549 cells. Oridonin induced decrease in Bcl-2/Bax ratio and activation of caspase-3, while these processes were reversed by HGF, suggesting that HGF played an anti-apoptotic role in oridonin-induced A549 cell death. HGF-induced protective effect was partially attributed to the activation of nuclear factor (NF)-κB and cyclooxygenase 2 (COX-2), since the protective effect was abolished by inhibition of NF-κB or interruption of COX-2. Then the activated COX-2 could prevent cells from initiating the apoptotic response by promoting prostaglandin E2 (PGE2) release. Activation of NF-κB-COX-2 by HGF-treatment triggered the increase in Bcl-2/Bax ratio, inhibition of procaspase-3 cleavage, promotion of Ca²âº-independent intracellular phospholipase A2 (iPLA2) expression and augmentation of PGE2 release, leading to antagonizing oridonin-induced cell death in A549 cells. HGF-induced cell survival in response to oridonin administration was associated with the activation of c-Met-NF-κB-COX-2 and c-Met-Bcl-2-caspase-3 signaling pathways. iPLA2, downstream effector of caspase-3, also participated in these processes.

Activated O2(•−) and H2O2 mediated cell survival in SU11274-treated non-small-cell lung cancer A549 cells via c-Met-PI3K-Akt and c-Met-Grb2/SOS-Ras-p38 pathways.

The pharmacological activity of SU11274 is primarily due to its inhibition of hepotocyte growth factor receptor (c-Met) kinase overexpression. In this study, we demonstrated that the pathway involved in SU11274-induced autophagy was presumably through inhibition of c-Met and its down-stream pathways, including phosphatidylinositol 3-kinases ­ Akt (PI3K­Akt) and the growth factor receptor bound protein-2 / son of sevenless ­ Ras ­ p38 MAPK (Grb2/SOS­Ras­p38) pathway. SU11274 time-dependently induced the generation of superoxide anion (O2(•−)) and hydrogen peroxide (H2O2). There is a negative feedback loop between reactive oxygen species (ROS) induction and SU11274. Then, we investigated the role of ROS in protecting cells against SU11274-induced autophagic cell death in A549 cells. O2(•−) and H2O2 generation activated c-Met­PI3K­Akt and c-Met­Grb2/SOS­Ras­p38 signaling pathways, which were suppressed by O2(•−) scavenger superoxide dismutase (SOD) and H2O2 scavenger catalase. In conclusion, O2(•−) and H2O2 evoked cell resistance to SU11274 via activating c-Met­PI3K­Akt and c-Met­Grb2/SOS­Ras­p38 pathways in A549 cells. SU11274 also induced ROS generation in Caenorhabditis elegans.

Activation of ERK-p53 and ERK-mediated phosphorylation of Bcl-2 are involved in autophagic cell death induced by the c-Met inhibitor SU11274 in human lung cancer A549 cells.

SU11274, a small molecule inhibitor of c-Met, was reported to induce apoptosis in human non-small-cell lung cancer (NSCLC) cells. However, SU11274-mediated autophagy in NSCLC cells has rarely been reported. The aim of this study was to elucidate the molecular mechanisms mediating SU11274-induced autophagy in NSCLC A549 cells. Here we reported that SU11274-induced autophagy was accompanied with an increase in the conversion of LC3-I to LC3-II and up-regulation of Beclin-1 expression. Subsequently, we also found that small interfering RNA against c-Met induced A549 cell autophagy while promotion of c-Met by hepatocyte growth factor (HGF) suppressed A549 cell autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed SU11274-induced cell death, suggesting that SU11274-induced autophagy caused cell death. Further study showed that ERK and p53 were activated after SU11274 treatment. Interruption of ERK and p53 activities decreased SU11274-induced autophagy, and blocking of ERK by the specific inhibitor PD98059 suppressed SU11274-induced p53 activation. Moreover, ERK activation upregulated Beclin-1 expression through induction of Bcl-2 phosphorylation, but p53 did not induce Bcl-2 phosphorylation. In conclusion, inhibition of c-Met induced autophagic cell death, which was associated with ERK-p53 activation and ERK-mediated Bcl-2 phosphorylation in A549 cells.