Yi Wei Chen

MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablation

Head and neck cancer (HNC) is a prevalent cancer worldwide. Let-7 has been shown to function as a tumour suppressor by regulating multiple oncogenic signalling pathways. However, the role of let-7 in head and neck cancer (HNC) and in HNC-associated tumour initiating cells (TIC) remains unclear. In this study, we first demonstrated that let-7a expression was significantly decreased but that Nanog/Oct4 expression was increased in HNC tissues as compared to adjacent normal cells. Expression of let-7a in recurrent HNC tissue and in regional metastatic lymph nodes of HNC patients was also significantly decreased, but Nanog/Oct4 expression was increased as compared to the expression levels in the parental tumours. Consistently, the stemness genes were significantly up-regulated and let-7a was down-regulated in HNC-ALDH1(+) cells relative to HNC-ALDH1(-) cells. Furthermore, lentiviral-mediated let-7a overexpression could significantly inhibit the stemness signature and the chemoresistant abilities of HNC-ALDH1(+) cells. Most importantly, overexpression of let-7 or knockdown of Nanog in ALDH1(+) cells effectively blocked tumour metastasis and significantly prolonged survival time in ALDH1(+)-transplanted immunocompromised mice. Overall, restoration of let-7a in HNC and HNC-TIC may be a new approach for the therapeutic treatment of HNC in the future. These results show that let-7a negatively modulates the expression of stemness genes and plays a role as a tumour suppressor in HNC by eliminating the putative HNC-TIC population.

Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer‐derived CD133‐positive cells

Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin‐1 (CD133)‐positive lung cancer cells.

Epithelial-mesenchymal transition transcription factor ZEB1/ZEB2 co-expression predicts poor prognosis and maintains tumor-initiating properties in head and neck cancer.

OBJECTIVESnBoth epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties may be involved in metastasis, which contributes to the high mortality rate of patients with head and neck cancers (HNCs). However, the mechanisms through which the EMT transcription factors ZEB1 and ZEB2 regulate HNC are still unclear.nnnMETHODSnTumor initiating capability of HNC-CH133(+) cells with ZEB1/2 knockdown or co-overexpression was presented in vitro and in vivo.nnnRESULTSnIn the present study, we demonstrated that ZEB1/ZEB2 expression was significantly increased in HNC-CD133(+) CSC-like cells compared with HNC-CD133(-) cells. The small interfering RNA (siRNA)-mediated co-knockdown of ZEB1 and ZEB2 (siZEB1/2) in HNC-CH133(+) cells suppressed their CSC-like properties, including self-renewal ability, the expression of stemness markers, and drug resistance. In contrast, the co-overexpression of ZEB1/ZEB2 in HNC-CD133(-) cells enhanced their sphere-forming ability and increased the percentage of CD44-positive cells and side population cells. In vivo studies showed that the delivery of siZEB1/2 to xenograft tumors in nude mice reduced tumor growth and the rate of distant metastasis. In clinical samples, the levels of ZEB1/ZEB2 expression were low in local lesions but high in metastatic lymph nodes in HNC tissues. Patients with tumors that co-expressed ZEB1(high) and ZEB2(high) had especially poor survival rates.nnnCONCLUSIONnTherapies targeting ZEB1/ZEB2 in HNC-CD133(+) cells may provide a new approach for HNC therapy in the future.

Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3 UTR of IL-6. In addition, miR142-3p also targets the 3 UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells

ObjectsCyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of tumors, including medulloblastoma (MB). CD133, a transmembrane glycoprotein, has been suggested as a marker for cancer stem cells in brain tumors. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the effects of ionizing radiotherapy (IR) on medulloblastoma-derived CD133-positive cells (MB-CD133+).Materials and methodsMB-CD133+ were isolated from two medulloblastoma cell lines (Daoy and UW228). Then, they were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, soft agar, radiosensitivity, colony formation, and apoptotic activity in MB-CD133+ treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated.ResultsMB-CD133+ showed the self-renew ability to form sphere bodies in vitro and regenerate tumors in vivo. The levels of COX-2 mRNA and protein in MB-CD133+ were significantly higher than those in MB-CD133−. The treatment of 30xa0μM celecoxib could effectively inhibit the abilities of cell proliferation and colony formation and increase IR-induced apoptosis in treated MB-CD133+. Furthermore, in vivo study demonstrated that celecoxib significantly enhanced radiosensitivity in MB-CD133+-transplanted grafts. Notably, xenotransplantation analysis demonstrated that the treatment of celecoxib could further suppress the expressions of angiogenic and stemnness-related genes in treated MB-CD133+ grafts of SCID mice.ConclusionsCelecoxib presents the potential of radiosensitizing effect in MB-derived cancer stem cells. Therefore, it should be warranted in future trials to enhance the radiotherapeutic effects in MB patients.

MicroRNA as a Novel Modulator in Head and Neck Squamous Carcinoma

MicroRNAs have emerged as important regulators of cell proliferation, development, cancer formation, stress responses, cell death, and other physiological conditions in the past decade. On the other hand, head and neck cancer is one of the top ten most common cancers worldwide. Recent advances in microRNAs have revealed their prominent role in regulating gene expression and provided new aspects of applications in diagnosis, prognosis, and therapeutic strategies in head and neck squamous carcinoma. In the present paper, we focus on microRNAs showing significant differences between normal and tumor cells or between cells with differential ability of metastasis. We also emphasize specific microRNAs that could modulate tumor cell properties, such as apoptosis, metastasis, and proliferation. These microRNAs possess the potential to be applied on clinical therapy in the future.

Spontaneous intramural intestinal haematoma

An 83-year-old man presented with a 3-day history of progressive abdominal pain and vomiting. He had a 20year history of hypertension and atrial fibrillation andwas taking antihypertensive agents and warfarin. The physical examination showed diffuse abdominal tenderness without rigidity. The routine complete blood count, serum biochemistry profiles were unremarkable except for an increased C reactive protein and prolonged prothrombin time. A plain abdominal radiograph showed distended small bowel loops (Fig. 1). Computed tomography (CT) of the abdomen, without i.v. contrast, showed marked thickening of the wall of the upper jejunum (Fig. 2). The density of the thickened bowel wall ranged from 40 to 60 Hounsfield Units (HU), similar to the density of blood in the abdominal aorta. Anticoagulant-induced intramural intestinal haematomawas diagnosed. The patient received conservative treatment with i.v. fluids and was discharged after7 days.A follow-upabdominalCTscanshowed that the intramural intestinal haematoma had largely resolved (Fig. 3).Hehashadno recurrences and continues todowell. Spontaneous intramural intestinal haematoma is a rare complication of anticoagulant therapy. It is often not suspected clinically and the diagnosis is usually made after abdominal imaging or when exploratory laparotomy is carried out. The non-contrast CT appearance of spontaneous intramural intestinal haematoma was originally described by Plojoux et al. as a hyperdense bowel wall with density ranging from 50 to 80 HU, depending on the time interval between the onset of bleeding and the CT examination. The following CT characteristics should suggest the diagnosis: circumferential wall thickening, intramural hyperdensity, luminal narrowing and intestinal obstruction. In general, conservative therapy is the treatment of choice, whereas surgical intervention is indicated

Clinical considerations and surgical approaches for low-grade gliomas in deep hemispheric locations: thalamic lesions

BackgroundTumors with epicenter in the thalamus occur in about 4xa0% of pediatric brain tumors. The histological diagnosis is mainly gliomas. Among them, low-grade glioma (LGG) constituted of a significant entity of the tumors (Cuccia et al., Childs Nerv Syst 13:514–521, 1997; Puget et al., J Neurosurg 106:354–362, 2007; Bernstein et al., J Neurosurg 61:649–656, 1984; Bilginer et al., Childs Nerv Syst 30:1493–1498, 2014). Since Kelly’s report in 1989, >90xa0% resection of thalamic tumors were achieved in reported series (Ozek and Ture, Childs Nerv Syst 18:450–6, 2002; Villarejo et al., Childs Nerv Syst 10:111–114, 1994; Moshel et al., Neurosurgery 61:66–75, 2007; Albright, J Neurosurg 100(5 Suppl Pediatrics): 468–472, 2004; Kelly, Neurosurgery 25:185–195, 1989; Drake et al., Neurosurgery 29: 27–33, 1991).Materials and methodsSixty-nine cases of thalamic tumors in children were retrospectively reviewed. There were 25 cases of LGGs. We analyzed our experience and correlated it with reported series.ResultsSumming up of 4 reported series and the present series, there were 267 cases of thalamic tumors in children. Among these tumors, 107 (40.1xa0%) were LGGs and 91 (34.1xa0%) were low-grade astrocytomas (LGAs). In the present series, all of the 25 LGGs were LGAs that consisted of 11 pilocytic astrocytomas (PAs) and 14 diffuse astrocytomas (DAs). Six cases received biopsy sampling only. The remaining 19 cases received different degrees of surgical resection via several approaches. Radical (>90xa0%) resection was achieved better in PAs comparing with DAs. There was no operative mortality. Two patients had increased neurological deficits. In a mean follow-up period of 11.9xa0years, three patients died of tumor progression and one patient died of anaplastic change. The 5- and 10-year overall survival (OS) was 87.1 and 87.1xa0%, respectively.ConclusionThalamic LGGs are mainly LGAs and are indolent. The rate of >90xa0% resection was relatively low in the present series. By applying contemporary diagnostic MRI studies, surgical facilities, and appropriate approaches in selective cases, we may try maximum neuroprotective radical (>90xa0%) resection.

Factors affecting survival of medulloblastoma in children: the changing concept of management

Medulloblastoma (MB) is a type of malignant tumor arising only in the cerebellum that was first defined by Cushing and Bailey in 1920s. In this review paper, we trace the evolution of risk stratification and the correlated changing concept of management in the past years. Outcome analysis of the hospital series of the Taipei Veterans General Hospital, Cheng Hsin General Hospital, and Taipei Medical University Hospital was performed to correlate prognostic indicators with reported studies. The purpose is to provide clues for age-specific and risk-adjusted optimal, effective, but beneficial and protective treatment strategies of these tumors in children.

Significance of cyclin D1 overexpression in progression and radio-resistance of pediatric ependymomas

Due to the limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for ependymoma treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy. Understanding the mechanism of therapeutic failure caused by radio-resistance is, therefore, crucial in ependymoma treatment. Here we retrospectively analyze clinic-pathological factors in 82 cases of ependymoma less than 20 years old and identify radio-resistant genes through gene expression microarray followed by qRT-PCR validation and immunohistochemistry staining. Thirty-one out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross-total resection is the single significant prognostic factor for longer 10 years PFS and OS in the multivariant analysis (p<0.05). According to the microarray analysis, CCND1 is up-regulated in supratentorial and infratentorial ependymomas and is associated with DNA repair. We demonstrated that 24 primary and 16 recurrent ependymomas were up-regulated, and 5 out of 7 paired samples exhibited higher CCND1 expression in recurrent tumors. We also found RAD51, another DNA repair gene, was up-regulated in supratentorial and infratentorial ependymomas. Knocking down CCND1 reduced cell proliferation and repressed several genes associated with S-phase and DNA repair. Homologous recombination activities of DNA repair were significantly decreased in CCND1-deficient cells while the level of γH2AX was increased after irradiation. In summary, these observations suggest a robust role of CCND1 in regulating cell proliferation and radio-resistance in ependymomas, providing a potential therapeutic target for pediatric ependymomas.