Conghua Xie

Nasopharyngeal carcinoma risk by histologic type in central China: Impact of smoking, alcohol and family history

The role of cigarette smoking, alcohol use, family history of cancer and the interaction of cigarettes and family history in the etiology of Nasopharyngeal carcinoma (NPC) in general and within each histologic type are unclear. We conducted a case‐control study among 1,044 Han Chinese patients with NPC and 1,095 Han Chinese cancer‐free control subjects. Logistic regression was used to analyze the association between histologic type of NPC and cigarette smoking, alcohol drinking and family history. The results indicated that NPC was significantly associated with cigarette smoking [adjusted odds ratio (OR) = 2.97, 95% confidence interval (CI), 2.38–3.70], and the association exhibited a dose‐response relationship for intensity, duration, and cumulative consumption of cigarettes (ptrend < 0.0001 for intensity, duration and cumulative consumption of cigarettes). Positive family history of cancer led to a significant 12‐fold elevated risk of NPC (adjusted OR = 12.95, 95% CI, 7.12–23.54) and acted jointly with cigarettes in contributing to NPC risk (adjusted OR = 56.68, 95% CI, 17.25–186.19). The association of NPC risk with cigarettes was stronger for nonkeratinizing carcinoma than for keratinizing squamous cell carcinoma (KSCC), whereas family history was more closely associated with KSCC. NPC risk was not associated with alcohol consumption. Our study demonstrated that cigarette smoking and family history of cancer could serve independently and jointly as risk factors for etiology of NPC and might affect the risk of histology‐specific NPC differently. This knowledge may help facilitate comprehension of NPC etiology in general as well as within each histologic type, and thereby improve prevention efforts.

Frizzled-8 as a putative therapeutic target in human lung cancer.

Lung cancer is the leading cause of cancer related deaths worldwide. It is necessary to better understand the molecular mechanisms involved in lung cancer in order to develop more effective therapeutics for the treatment of this disease. Recent reports have shown that Wnt signaling pathway is important in a number of cancer types including lung cancer. However, the role of Frizzled-8 (Fzd-8), one of the Frizzled family of receptors for the Wnt ligands, in lung cancer still remains to be elucidated. Here in this study we showed that Fzd-8 was over-expressed in human lung cancer tissue samples and cell lines. To investigate the functional importance of the Fzd-8 over-expression in lung cancer, we used shRNA to knock down Fzd-8 mRNA in lung cancer cells expressing the gene. We observed that Fzd-8 shRNA inhibited cell proliferation along with decreased activity of Wnt pathway in vitro, and also significantly suppressed A549 xenograft model in vivo (p<0.05). Furthermore, we found that knocking down Fzd-8 by shRNA sensitized the lung cancer cells to chemotherapy Taxotere. These data suggest that Fzd-8 is a putative therapeutic target for human lung cancer and over-expression of Fzd-8 may be important for aberrant Wnt activation in lung cancer.

Th2-like immune response in radiation-induced lung fibrosis

Pulmonary fibrosis is a common delayed side effect of radiation therapy. Since its mechanism is almost unknown, little can be done to prevent or treat it. Th2 cytokines have been clearly implicated as mediators of asthma, and evidence is mounting that type 2 immune responses may also promote the development of pulmonary fibrosis. The aim of this study was to investigate whether Th2-like immune responses account for the development and progression of chronic radiation pulmonary fibrosis. C57BL/6 mice received thoracic irradiation of 12 Gy and were sacrificed at 1 h and 1, 2, 4, 8, 16 and 24 weeks post-irradiation (p.i.). We assayed the expression of IL-13 in serum, and the expression of hydroxyproline and the mRNA and protein of GATA-3 and Arg-1 in lung tissue. mRNA and protein analysis revealed the expression of these Th2-immune response-associated factors (GATA-3, IL-13 and Arg-1) in mice after irradiation. Without causing conspicuous fibrotic pathological changes at the early post-irradiation phase (1 and 2 weeks p.i.), a Th2 profile was confirmed by significantly elevated expression of Th2-specific transcription factor GATA-3 mRNA (P<0.01). Protein analysis confirmed the GATA-3 mRNA expression. Following significantly elevated expression of hydroxyproline (P<0.01) at 16 weeks p.i., IL-13 and Arg-1 expression reached maximal values in serum and lung tissue and maintained high levels up to 24 weeks p.i., respectively (P<0.01). Our data indicate that lung irradiation induces Th2 polarization. Furthermore, Th2-like immune response may take part in radiation-induced pulmonary fibrosis (RILF), and GATA-3 may play an important role in promoting RILF. Thus, GATA-3 may be an important target for the treatment of RILF.

Novel, chimeric, cancer-specific, and radiation-inducible gene promoters for suicide gene therapy of cancer†

Although the promoter of the human telomerase reverse transcriptase (hTERT) gene has been widely used in gene therapy for targeted cancer cells, it has some limitations for clinical use because of its low activity and potential toxicity to certain normal cells. To overcome these defects, the authors generated novel chimeric hTERT promoters that contained the radiation‐inducible sequence CC(A/T)6GG (known as CArG elements).

Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma

BackgroundGene therapy is a promising therapeutic approach for cancer. Targeted expression of desired therapeutic proteins within the tumor is the best approach to reduce toxicity and improve survival. This study is to establish a more effective and less toxic gene therapy of cancer.MethodsCombined gene therapy strategy with recombinant adenovirus expressing horseradish peroxidase (HRP) mediated by human telomerase reverse transcriptase (hTERT) promoter (AdhTERTHRP) and murine interleukin-12 (mIL-12) under the control of Cytomegalovirus (CMV) promoter (AdCMVmIL-12) was developed and evaluated against Lewis lung carcinoma (LLC) both in vivo and in vitro. The mechanism of action and systemic toxicities were also investigated.ResultsThe combination of AdhTERTHRP/indole-3-acetic acid (IAA) treatment and AdCMVmIL-12 resulted in significant tumor growth inhibition and survival improvement compared with AdhTERTHRP/IAA alone (tumor volume, 427.4 ± 48.7 mm3vs 581.9 ± 46.9 mm3, p = 0.005 on day 15; median overall survival (OS), 51 d vs 33 d) or AdCMVmIL-12 alone (tumor volume, 362.2 ± 33.8 mm3vs 494.4 ± 70.2 mm3, p = 0.046 on day 12; median OS, 51 d vs 36 d). The combination treatment stimulated more CD4+ and CD8+ T lymphocyte infiltration in tumors, compared with either AdCMVmIL-12 alone (1.3-fold increase for CD4+ T cells and 1.2-fold increase for CD8+ T cells, P < 0.01) or AdhTERTHRP alone (2.1-fold increase for CD4+ T cells and 2.2-fold increase for CD8+ T cells, P < 0.01). The apoptotic cells in combination group were significantly increased in comparison with AdCMVmIL-12 alone group (2.8-fold increase, P < 0.01) or AdhTERTHRP alone group (1.6-fold increase, P < 0.01). No significant systematic toxicities were observed.ConclusionsCombination gene therapy with AdhTERTHRP/IAA and AdCMVmIL-12 could significantly inhibit tumor growth and improve host survival in LLC model, without significant systemic adverse effects.

The Relationship Between Cancer Pain and Quality of Life in Patients Newly Admitted to Wuhan Hospice Center of China

To evaluate the relationship between pain and quality of life (QoL) in patients newly admitted to Wuhan Hospice Center, China. A total of 1,634 patients were analyzed in this retrospective study. A Numerical Rating Scale and Chinese-QoL instrument were used to assess pain score and QoL, respectively. Most patients experienced moderate to severe pain, which significantly impaired QoL. The pain was significantly correlated with appetite, mood, sleep, fatigue, pain intensity, daily activity, side effect, general appearance, and support from family. But there was no correlation with support from society, understanding of cancer, or attitude toward treatment. In our study, the relationship between pain and QoL was found to be reciprocal. The staff can offer a multidisciplinary care perspective for improving hospice care for this special group of population.

ROCK Cooperated with ET-1 to Induce Epithelial to Mesenchymal Transition through SLUG in Human Ovarian Cancer Cells

The Rho-associated serine-threonine protein kinase (ROCK) is a downstream effector of Rho GTPases that is frequently activated in the epithelial to mesenchymal transition (EMT) of human ovarian cancer cells. On the other hand, endothelin-1 (ET-1) and its receptor endothelin A receptor (ETAR) are overexpressed in primary and metastatic ovarian carcinoma, which suggests that ET-1 promotes tumor dissemination. Hence, two human ovarian carcinoma cell lines, SK-OV-3 and CaOV3, were chosen to study the effects of ET-1/ETAR and ROCK in promoting EMT of ovarian cancer cells. We found that ET-1 exposure induced EMT of SK-OV-3 and CaOV3 by monitoring cells morphology, enhanced fibronectin, and reduced E-cadherin protein. At the same time, ET-1/ETAR enhanced the level of transcription of SLUG a transcriptional repressor of E-cadherin. More importantly, a constitutively active mutant of ROCK enhanced the transcription of SLUG by stimulating SLUG promoter activity. Furthermore, ROCK inhibitor Y27632 reversed the increase in fibronectin induced by ET-1/ETAR. Our data suggest that ROCK cooperated with ET-1/ETAR to promote EMT of human ovarian carcinoma cells through upregulation of SLUG mRNA.

Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells.

The selective toxicity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against tumor cells makes it a potential targeted drug for treating non-small cell lung carcinomas (NSCLC). However, the majority of established human NSCLC cell lines are either partially or completely resistant to TRAIL, resulting in the limitation for clinical use of rhTRAIL and its agonistic antibodies. In this study, compared to TRAIL-sensitive H460 cell line, TRAIL-resistant A549 cell line showed a similar expression level of DR5 and a higer expression level of DR4. It indicates that there is no positive correlation between the expression levels of death receptors and sensitivity to TRAIL. However, tests on A549 cells with DR4 siRNA transfection revealed that DR4-competitive binding to TRAIL could not affect the capacity of TRAIL in inducing apoptosis. Instead, further studies found that the aggregation of DR4 and DR5 in lipid rafts only occured in H460 cells with TRAIL pretreatment. It suggested that the TRAIL-induced redistribution of DR4 and DR5 in lipid rafts contributed to the sensitivity to TRAIL in TRAIL-sensitive NSCLC H460 cell line, which was also confirmed by intervention tests of the cholesterol-sequestering agent nystatin.

Efficient inhibition of human telomerase activity by antisense oligonucleotides sensitizes cancer cells to radiotherapy

AbstractAim:To investigate the effect of the antisense oligonucleotides (ASODN) specific for human telomerase RNA (hTR) on radio sensitization and proliferation inhibition in human neurogliocytoma cells (U251).Methods:U251 cells were transfected with hTR ASODN or nonspecific oligonucleotides (NSODN). Before and after irradiation of 60Co-γ ray, telomerase activity was assayed by telomeric repeat amplification protocol (TRAP-PCR-ELISA), and DNA damage and repair were examined by the comet assay. The classical colony assay was used to plot the cell-survival curve, to detect the D0 value.Results:hTR antisense oligonucleotides could downregulate the telomerase activity, increase radiation induced DNA damage and reduce the subsequent repair. Furthermore, it could inhibit the proliferation and decrease the D0 value which demonstrates rising radiosensitivity. However, telomere length was unchanged over a short period of time.Conclusion:These findings suggest that an ASODN-based strategy may be used to develop telomerase inhibitors, which can efficiently sensitize radiotherapy.

Angelica sinensis Down-regulates Hydroxyproline and Tgfb1 and Provides Protection in Mice with Radiation-Induced Pulmonary Fibrosis

Abstract Han, G., Zhou, Y. F., Zhang, M. S., Cao, Z., Xie, C. H., Zhou, F. X., Peng, M. and Zhang, W. J. Angelica sinensis Down-regulates Hydroxyproline and Tgfb1 and Provides Protection in Mice with Radiation-Induced Pulmonary Fibrosis. Radiat. Res. 165, 546–552 (2006). Pulmonary fibrosis is a common delayed side effect of radiation therapy, and it has a poor prognosis. Tgfb1 is a potent chemoattractant for fibroblasts and stimulates the production of collagen, the protein that contains hydroxyproline. Since collagen is by far the most abundant protein in the lung, comprising 60–70% of the tissue mass, analysis of the hydroxyproline content in lung tissues provides a reliable quantitative index for pulmonary fibrosis. Thus hydroxyproline and Tgfb1 may be involved in the development of fibrosis. In this study, we investigated radiation-induced pulmonary fibrosis in a mouse model. C57BL/6 mice were assigned into four groups: no treatment, treated with Angelica sinensis treated only, X-irradiated only (a single fraction of 12 Gy to the thorax), and Angelica sinensis treatment plus radiation. We assayed expression of hydroxyproline and the mRNA and protein of Tgfb1 in the four groups. We found that Angelica sinensis down-regulated the production of Tgfb1 and hydroxyproline in mice with radiation-induced pulmonary fibrosis. This study has demonstrated for the first time that Angelica sinensis inhibits the progress of radiation-induced pulmonary fibrosis, possibly by down-regulating the expression of the proinflammatory cytokine Tgfb1. These data suggest that Angelica sinensis may be useful in preventing and/or treating radiation-induced pulmonary fibrosis in the clinic.