Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas.</p> <p>Methods</p> <p>We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (<it>MT-ATP6, MT-CO1, MT-CYB, MT-ND1</it>, <it>MT-ND6</it>, and <it>MT-RNR1</it>) were quantified in 62 cancer tissues by real-time RT-PCR.</p> <p>Results</p> <p>Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene <it>RNR1 </it>might be used as a predictor of tumour sensitivity to chemotherapy.</p> <p>Conclusion</p> <p>In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.</p

Retinoic acid receptor &alpha; facilitates human colorectal cancer progression via Akt and MMP2 signaling

Gui-Li Huang,1 Qing-Xi Chen,2 Jia-Jia Ma,1 Si-Yao Sui,1 Yu-Ning Wang,1 Dong-Yan Shen31Agricultural Product Storage and Processing Laboratory, Suzhou Academy of Agricultural Sciences, Suzhou, 215155, People&rsquo;s Republic of China; 2State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, People&rsquo;s Republic of China; 3Biobank, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People&rsquo;s Republic of ChinaPurpose: Retinoic acid &alpha; (RAR&alpha;) is overexpressed in various tumors and facilitates cancer progression. Although RAR&alpha; has been shown to facilitate colorectal cancer (CRC) progression, more efforts to characterize mechanisms of RAR&alpha; in CRC are needed in order to develop better target-based drugs for tumor therapy. Methods: RAR&alpha; expression in CRC was assessed by IHC. EdU, QPCR, Western blotting, dual-luciferase reporter assay and ChIP were performed to explore the role of RAR&alpha; in CRC and the mechanism involoved.Results: Here, we show an overexpression of RAR&alpha; in 73.5% (i.e., 25 of 34 human CRC specimens). RAR&alpha; knockdown decreased cell proliferation, migration, and invasion. Such phenotypic manifestations can be correlated to lowered activation of Akt and expression of PCNA (proliferating cell nuclear antigen) as well as MMP2 (matrix metallopeptidase). Mechanistically, RAR&alpha; facilitates CRC growth through Akt signaling activation to cause levels of PCNA to be upregulated. Furthermore, RAR&alpha; promotes migration and invasion of CRC cells by directly recruiting the MMP2 promoter to enhance the expression of MMP2.Conclusions: These findings demonstrate that CRC carcinogenesis is promoted by RAR&alpha; via an enhanced Akt signaling and by increasing MMP2 transcription. CRC therapy can examine the use of RAR&alpha; as a prospective molecular target.Keywords: colorectal cancer, RAR&alpha;, proliferation, PCNA, MMP

Intranasal vaccination of recombinant adeno-associated virus encoding receptor-binding domain of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein induces strong mucosal immune responses and provides long-term protection against SARS-CoV infection

We have previously reported that a subunit protein vaccine based on the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein and a recombinant adeno-associated virus (rAAV)-based RBD (RBD-rAAV) vaccine could induce highly potent neutralizing Ab responses in immunized animals. In this study, systemic, mucosal, and cellular immune responses and long-term protective immunity induced by RBD-rAAV were further characterized in a BALB/c mouse model, with comparison of the i.m. and intranasal (i.n.) routes of administration. Our results demonstrated that: 1) the i.n. vaccination induced a systemic humoral immune response of comparable strength and shorter duration than the i.m. vaccination, but the local humoral immune response was much stronger; 2) the i.n. vaccination elicited stronger systemic and local specific cytotoxic T cell responses than the i.m. vaccination, as evidenced by higher prevalence of IL-2 and/or IFN-γ-producing CD3+/CD8+ T cells in both lungs and spleen; 3) the i.n. vaccination induced similar protection as the i.m. vaccination against SARS-CoV challenge in mice; 4) higher titers of mucosal IgA and serum-neutralizing Ab were associated with lower viral load and less pulmonary pathological damage, while no Ab-mediated disease enhancement effect was observed; and 5) the vaccination could provide long-term protection against SARS-CoV infection. Taken together, our findings suggest that RBD-rAAV can be further developed into a vaccine candidate for prevention of SARS and that i.n. vaccination may be the preferred route of administration due to its ability to induce SARS-CoV-specific systemic and mucosal immune responses and its better safety profile. Copyright © 2008 by The American Association of Immunologists, Inc.link_to_OA_fulltex