Hong Sui

UCA1, a long non-coding RNA up-regulated in colorectal cancer influences cell proliferation, apoptosis and cell cycle distribution

Summary Colorectal cancer (CRC) is one of the most common cancers worldwide. Long non-coding RNAs (lncRNAs) have been shown to play important regulatory roles in cancer biology, and functional lncRNAs can be used for cancer diagnosis and prognosis. One lncRNA that has attracted significant attention is urothelial carcinoma-associated 1 (UCA1), which is significantly up-regulated in most tumour tissues and cancer cells. However, the contributions of UCA1 to CRC remain largely unknown. Thus, the aim of the current study was to investigate the clinical significance and biological function of UCA1 in CRC. First, we evaluated whether UCA1 is detectable or altered in CRC tissues or cell lines compared to adjacent normal tissues or normal cell lines by quantitative real-time polymerase chain reaction. The potential relationship between UCA1 levels in tumour tissues and the clinicopathological features of CRC was then investigated. Finally, we assessed whether UCA1 influences cell proliferation, apoptosis, cell cycle distribution and migration in vitro. Our results demonstrated that UCA1 levels were markedly increased in CRC tissues and cells compared to controls, and this high level of UCA1 expression was significantly correlated with larger tumour size, less differentiated histology and greater tumour depth. In addition, patients with high UCA1 expression had a significantly poorer prognosis than those with low UCA1 expression. Moreover, UCA1 was found to influence the proliferation, apoptosis and cell cycle progression of CRC cells. These data suggest an important role for UCA1 in the molecular aetiology of CRC and suggest a potential application for UCA1 in CRC diagnosis, progression and therapy.

A Polymorphism at the 3'-UTR Region of the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor, Anastrozole, in Metastatic Breast Carcinoma

Estrogen-related genes and the fat mass and obesity-associated (FTO) gene play a critical role in estrogen metabolism, and those polymorphisms are associated with a poor prognosis in breast cancer. However, little is known about the association between these polymorphisms and the efficacy of anastrozole. The aim was to investigate the impact of the genetic polymorphisms, CYP19A1, 17-β-HSD-1 and FTO, on the response to anastrozole in metastatic breast carcinoma (MBC) and to evaluate the impact of those polymorphisms on various clinicopathologic features. Two-hundred seventy-two women with hormone receptor-positive MBC treated with anastrozole were identified retrospectively. DNA was extracted from peripheral blood and genotyped for five variants in three candidate genes. Time to progression was improved in patients carrying the variant alleles of rs4646 when compared to patients with the wild-type allele (16.40 months versus 13.52 months; p = 0.049). The rs4646 variant alleles were significantly associated with longer overall survival (37.3 months versus 31.6 months; p = 0.007). This relationship was not observed with the rs10046, rs2830, rs9926298 and rs9939609 polymorphisms. The findings of this study indicate that rs4646 polymorphism in the CYP19A1 gene may serve as a prognostic maker of the response to anastrozole in patients with MBC who are treated with anastrozole.

Initiation of apoptosis, cell cycle arrest and autophagy of esophageal cancer cells by dihydroartemisinin.

Dihydroartemisinin (DHA) has recently been shown anti-tumor activity in various cancer cells. However, its effect on esophageal cancer remains unclear. In this study, for the first time, we demonstrated that DHA reduced viability of esophageal cancer cells in a dose-dependent manner. The mechanism was at least partially due to DHA induced apoptosis by upregulating the expression of Bax, downregulating Bcl-2, Bcl-xL and Procaspase-3, and increasing caspase-9 activation, induced cell cycle arrest by downregulating cyclin E, CDK2 and CDK4. Furthermore, we firstly found that DHA induced autophagy in cancer cells. We concluded DHA might be a novel agent against esophageal cancer.

MiR-590-5p inhibits colorectal cancer angiogenesis and metastasis by regulating nuclear factor 90/vascular endothelial growth factor A axis

Altered expression of microRNA-590-5p (miR-590-5p) is involved in tumorigenesis, however, its role in colorectal cancer (CRC) remains to be determined. In this study, we focused on examining the effects of different expression levels of miR-590-5p in cancer cells and normal cells. Results showed that there are lower expression levels of miR-590-5p in human CRC cells and tissues than in normal control cells and tissues. Similarly, in our xenograft mouse model, knockdown of miR-590-5p promoted the progression of CRC. However, an overexpression of miR-590-5p in the mice inhibited angiogenesis, tumor growth, and lung metastasis. Nuclear factor 90 (NF90), a positive regulator of vascular endothelial growth factor (VEGF) mRNA stability and protein synthesis, was shown to be a direct target of miR-590-5p. The overexpression of NF90 restored VEGFA expression and rescued the loss of tumor angiogenesis caused by miR-590-5p. Conversely, the NF90-shRNA attenuated the increased tumor progression caused by the miR-590-5p inhibitor. Clinically, the levels of miR-590-5p were inversely correlated with those of NF90 and VEGFA in CRC tissues. Furthermore, knockdown of NF90 lead to a reduction of pri-miR-590 and an increase of mature miR-590-5p, suggesting a negative feedback loop between miR-590-5p and NF90. Collectively, these data establish miR-590-5p as an anti-onco-miR that inhibits CRC angiogenesis and metastasis through a new mechanism involving NF90/VEGFA signaling axis, highlighting the potential of miR-590-5p as a target for human CRC therapy.

Dihydroartemisinin Accentuates the Anti- Tumor Effects of Photodynamic Therapy via Inactivation of NF-κB in Eca109 and Ec9706 Esophageal Cancer Cells

Background: Photodynamic therapy (PDT) is a new treatment for esophageal cancer which has been shown to be effective in the elimination of tumor. However, PDT could induce the activation of nuclear factor-kappa B (NF-κB) in many photosensitizers based PDT, which plays a negative role in PDT. In addition, our previous results have shown that dihydroartemisinin (DHA), which was the most potent one of artemisinin derivatives, has anticancer activity in esophageal cancer cells. Methods: Cell viability was determined by MTT analysis, and apoptosis was evaluated by flow cytometry. Nuclear extract was obtained for determining NF-κB DNA-binding activity, while total protein extract obtained for downstream gene expression by western blot. Results: We demonstrated DHA enhanced PDT-induced growth inhibition and apoptosis in both human esophageal cancer cell lines Eca109 and Ec9706 in vitro. The mechanism was at least partially due to DHA deactivated PDT-induced NF-κB activation, so as to decrease tremendously the expression of its target gene Bcl-2. Conclusion: Our results demonstrate that DHA augments PDT-induced growth inhibition and apoptosis in esophageal cancer cells, and that inactivation of NF-κB activity is a potential mechanism by which DHA sensitizes esophageal cancer cells to PDT-induced growth inhibition and apoptosis.

Cthrc1 overexpression is an independent prognostic marker in gastric cancer

Collagen triple helix repeat containing 1 (CTHRC1) was identified as a novel gene expressed in the adventitia and neointima on arterial injury and was found to be overexpressed in several malignant tumors, such as breast cancer and malignant melanoma. However, the expression of Cthrc1 and its role in gastric cancer progression remain unknown. We investigated the expression of the Cthrc1 protein by immunohistochemistry in 30 normal tissues from the control subjects and 166 gastric carcinomas and analyzed its correlation with various clinicopathological features, including patient outcome. Cthrc1 immunoreactivity was overexpressed in gastric carcinoma cases compared with normal tissues (P < .001). High Cthrc1 expression was found in 108 (65.06%) of these 166 carcinomas and was positively correlated with the American Joint Committee on Cancer stage classification, depth of gastric wall invasion, lymph node metastasis, lymphovascular space involvement, and recurrence but not with age, tumor site, and carcinoembryonic antigen level. Patients with high Cthrc1 expression had significantly poorer overall survival and disease-free survival compared with patients with low expression of Cthrc1 (P = .001 and P = .002, respectively). Multivariate analysis showed that high Cthrc1 expression was an independent prognostic factor for both overall survival and disease-free survival of patients with gastric carcinoma (both P = .005). These results showed that high Cthrc1 expression was associated with progression and prognosis of gastric carcinoma.

The anti-tumor effect of Newcastle disease virus HN protein is influenced by differential subcellular targeting

BackgroundImmunotherapy is emerging as a major player in the current standard of care for aggressive cancers such as non-small cell lung cancer (NSCLC). The Newcastle disease virus with its tumor-specific replicative and oncolytic abilities is a promising immunotherapeutic candidate. A DNA vaccine expressing the major immunogenic hemagglutinin-neuraminidase (HN) protein of this virus has shown promising results as an immunotherapeutic agent.MethodsIn the present study, three different DNA vaccine constructs encoding differentially targeted HN proteins (cytoplasmic or Cy-HN, secreted or Sc-HN and membrane-anchored or M-HN) were generated to evaluate their anti-tumor effect in vitro and in vivo.ResultsAlthough all three DNA constructs elicited an immune response, tumor-bearing mice intratumorally injected with M-HN demonstrated a significantly better anti-tumor effect than those injected with Cy-HN or Sc-HN. We also showed that this anti-tumor effect was mediated by higher lymphocyte proliferative response and CTL activity in mice intratumorally injected with M-HN.ConclusionThe membrane-anchored form of the HN protein appears to be an ideal candidate to develop as an immunotherapeutic agent for NSCLC.

Sonodynamically Induced Anti-tumor Effect of 5-Aminolevulinic Acid on Pancreatic Cancer Cells

Sonodynamic therapy (SDT), a promising modality for cancer treatment, involves the synergistic interaction of ultrasound and some chemical compounds termed sonosensitizers. However, its effect on pancreatic cancer cells remains unclear. In our study, we sought to identify the cytotoxic effects of ultrasound-activated 5-aminolevulinic acid on human pancreatic cancer Capan-1 cells. Cell viability was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) analysis; mitochondrial membrane potential was assessed using the fluorescent probe jc-1; apoptosis was evaluated by flow cytometry; cell morphology was investigated by scanning electron microscopy; apoptosis-related protein expression was analyzed by Western blot assay. We found that SDT significantly decreased the survival rate of cells, and this effect increased with 5-aminolevulinic acid concentration and ultrasound exposure time. The mechanism underlying the effect of SDT involves, in part, the induction of a conspicuous loss in mitochondrial membrane potential and, in part, the induction of apoptosis through upregulation of Bax expression, downregulation of Bcl-2 and increased activation of procaspase-3. These results indicate that the ultrasonically induced cell killing effect could be enhanced by 5-ALA and that the mitochondrial pathway might be involved in the cell damage process. We conclude that SDT is a promising new methodology for pancreatic cancer treatment.

NDV-D90 suppresses growth of gastric cancer and cancer-related vascularization

Recent reports suggest promises on using oncolytic Newcastle disease viruses (NDV) to treat different cancers, while the effects of a NDV-D90 strain on gastric cancer remain unknown. Here we showed that NDV-D90 induced gastric cancer cell apoptosis in a dose-dependent manner in 3 gastric cancer cell lines BGC-823, SGC-7901 and MKN-28. Pronounced reduction in cell invasion was detected in NDV-D90-treated BGC-823 and SGC-7901 cells, but not in MKN-28 cells. The increases in cell apoptosis and reduction in cell growth in NDV-D90-treated gastric cancer cells seemingly resulted from augmentation of p38 signaling and suppression of ERK1/2 and Akt signaling. In vivo, orthotopic injection of NDV-D90 impaired tumor growth and induced intratumoral necrosis. Tumor cells that had been pre-treated with NDV-D90 showed defect in development of implanted tumor. Moreover, NDV-D90 appeared to reduce gastric tumor vascularization, possibly through suppression of vascular endothelial growth factor A and Matrix Metallopeptidase 2. Together, our data suggest that NDV-D90 may have potential anti-cancer effects on gastric cancer.

Dihydroartemisinin Increases the Sensitivity of Photodynamic Therapy Via NF-κB/HIF-1α/VEGF Pathway in Esophageal Cancer Cell in vitro and in vivo

Background/Aims: Although photodynamic therapy (PDT) can relieve esophageal obstruction and prolong survival time of patients with esophageal cancer, it can induce nuclear factor-kappa B (NF-κB) activation in many cancers, which plays a negative role in PDT. Dihydroartemisinin (DHA), the most potent artemisinin derivative, can enhance the effect of PDT on esophageal cancer cells. However, the mechanism is still unclear. Methods: We generated stable cell lines expressing the super-repressor form of the NF-κB inhibitor IκBα and cell lines with lentivirus vector-mediated silencing of the HIF-1α gene. Esophageal xenograft tumors were created by subcutaneous injection of Eca109 cells into BALB/c nude mice. Four treatment groups were analyzed: a control group, photosensitizer alone group, light alone group, and PDT group. NF-κB expression was detected by an electrophoretic mobility shift assay, hypoxia-inducible factor α (HIF-1α) and vascular endothelial growth factor (VEGF) by real-time PCR, NF-κB, HIF-1α, and VEGF protein by western blot, and Ki-67, HIF-1α, VEGF, and NF-κB protein by immunohistochemistry. Results: PDT increased NF-κB activity and the gene expression of HIF-1α and VEGF in vitro and in vivo. In contrast, the DHA groups, particularly the combined DHA and PDT treatment group, abolished the effect. The combined treatment significantly inhibited tumor growth in vitro and in vivo. NF-κB activity and HIF-1α expression were also reduced in the stable IκBα expression group, whereas the former showed no change in HIF-1α-silenced cells. Conclusion: DHA might increase the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-κB/HIF-1α/VEGF pathway.