Cheng Hwai Tzeng

Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition

The epithelial–mesenchymal transition (EMT), one of the main mechanisms underlying development of cancer metastasis, induces stem-like properties in epithelial cells. Bmi1 is a polycomb-group protein that maintains self-renewal, and is frequently overexpressed in human cancers. Here, we show the direct regulation of BMI1 by the EMT regulator, Twist1. Furthermore, Twist1 and Bmi1 were mutually essential to promote EMT and tumour-initiating capability. Twist1 and Bmi1 act cooperatively to repress expression of both E-cadherin and p16INK4a. In patients with head and neck cancers, increased levels of both Twist1 and Bmi1 correlated with downregulation of E-cadherin and p16INK4a, and was associated with the worst prognosis. These results suggest that Twist1-induced EMT and tumour-initiating capability in cancer cells occurs through chromatin remodelling, which leads to unfavourable clinical outcomes.

RAC1 activation mediates Twist1-induced cancer cell migration.

Epithelial–mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1–let-7i–NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.

Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy.

The R521K polymorphism of epidermal growth factor receptor has attenuated affinity in ligand binding and proto‐oncogene induction, which may affect the efficacy of cetuximab. We analyzed the effect of this polymorphism on the outcome of 112 patients with KRAS wild‐type metastatic colorectal carcinoma treated with first‐line cetuximab plus FOLFOX‐4. The associations of this polymorphism with vascular endothelial growth factor (VEGF) expression and clinicopathologic characteristics were also examined. The results showed that the frequencies of the G/G, G/A, and A/A genotypes were 32.1% (n = 36), 42.9% (n = 48), and 25.0% (n = 28), respectively. A marked decrease in VEGF expression levels (66.7% vs 28.9%, P < 0.01) was observed in patients with 521A allele variants (Arg/Lys or Lys/Lys), which were associated with a decreased tumor size (55.6% vs 31.6%, P = 0.02), good histological differentiation (63.9% vs 85.5%, P = 0.01), decreased lymphovascular invasion (69.4% vs 39.5%, P < 0.01), and a higher response rate to cetuximab plus FOLFOX treatment (55.6% vs 78.9%, P = 0.01). In addition, this polymorphism was associated with a longer progression‐free period (P = 0.001) and overall survival (P = 0.001). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor. These data suggest that the R521K polymorphism of epidermal growth factor receptor, by reducing its activation and a consequential downregulation of its target genes, including VEGF, could be a key determinant of an increased response to cetuximab‐based chemotherapy and a longer survival for KRAS wild‐type colorectal carcinoma patients. (Cancer Sci 2012; 103: 791–796)

Prevalence and prognostic influence of genomic changes of EGFR pathway markers in synovial sarcoma

We aimed to study the prevalence and prognostic influence of epidermal growth factor receptor (EGFR) and its downstream effectors in synovial sarcoma (SS).

Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism

AbstractPurposeA dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer.MethodsFive colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray.Results Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT.ConclusionsTemsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT.

Novel polymorphisms in exons 6 and 7 of A/B alleles detected by polymerase chain reaction-single strand conformation polymorphism

Background and Objectives  The ABO blood group system is the most important blood group system in transfusion medicine. In addition to the major A, B and O alleles, many rare alleles have been defined. Polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and analysis by PCR sequence specific primers (SSP) are commonly conducted for genotyping but have the limitation of being unable to detect unknown substitution(s) in amplified DNA fragments, whereas PCR–single strand conformation polymorphism (SSCP) can be used for both.

Screening of anti-HTLV antibody in sera of normal individuals and patients with malignancies in Taiwan

In the present study an immunofluorescence using KH-2 cells as target cells, has been developed for the screening of 1200 serum samples from normal individuals and 450 of cases from patients with various malignancies. The positive anti-HTLV-I antibody rate in the former group is 0.083% (1/1200) and while in the latter it is found to be 1.8% (8/450) (including 3 adult T-cell leukemia/lymphoma cases of the 92 hematopoietic and 5 of 358 non-hematopoietic malignancies). The differences between the two groups are found to be significantly different (p value is less than 0.0001). In addition to the 3 adult T-cell leukemia/lymphoma cases, the 5 seropositive cancer patients are of 5 different diseases. We have searched for the adult T-cell leukemia virus antigen and the p19 core protein in lymphoid cells of seropositive persons and the only positive cases were from cells of two proven adult T-cell leukemia (ATL) patients. Our results suggest that Taiwan is not an endemic area of adult T-cell leukemia virus and that KH-2 cells may be used for the detection of anti-HTLV-I antibodies.

Too many platelets to cause compartment syndrome

An 86-year-old Taiwanese woman presented with a 1-week history of progressive swelling, pain and paresthesia of left forearm. Physical examination revealed extensive confluent hemorrhagic bullae on the arm (Figure 1a). Bleeding from other sites was absent. She denied any recent trauma but had undergone a toe amputation because of thrombotic gangrene 4 months ago. A complete blood count showed a white cell count of 15 700/mm3, hemoglobin level of 10.5 g/dl and a platelet count of 3 390 000/mm3. Prothrombin time was 12.9 s (normal …

Weekly CAF Chemotherapy for Advanced Breast Cancer Patients

In a prospective phase II study, 102 women with advanced breast cancer were treated with low doses of cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) at weekly intervals by intravenous injection. Seventy-five patients were evaluable for treatment response and the overall response rate was 52% (95% confidence interval, 41-63%). Of the evaluable patients, 15% had complete response and 37% had partial response. The median survival after therapy was 15.6 months, the median time to progression was 6.8 months and the median duration of response was 9.1 months. The main toxicities were mild vomiting and moderate myelosuppression. There was only 1 patient who experienced heart failure. Weekly CAF appears to have an efficacy with tolerable side effects comparable to standard CAF with an every-3-week schedule.

Effective salvage therapy of imatinib-resistant gastrointestinal stromal tumor with combination of imatinib and pegylated liposomal doxorubicin

Here we presented a 60-year-old Taiwanese man with advanced gastrointestinal stromal tumor. Disease progression was noted during imatinib treatment. Surgical resection was done and mutation analysis of KIT gene in all the resected tumors revealed deletion mutations of codons 558-565 in exon 11, whereas a missense mutation was also identified at codon 822 in exon 17 in one resected tumor. Patients disease was refractory to escalating dose of imatinib and dasatinb. Surprisingly, combination of imatinib with pegylated liposomal doxorubicin produced a substantial response and resulted in a 5-month progression free period for this imatinib-resistant gastrointestinal stromal tumor.