PubMed · 13999385
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H F WEBER. 1962. [Hypernephroma].. https://pubmed.ncbi.nlm.nih.gov/13999385/
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Ribonucleotide reductase is emerging as an important determinant of gemcitabine chemoresistance in human cancers. Activity of this enzyme, which catalyses conversion of ribonucleotide 5'-diphosphates to their 2'-deoxynucleotides, is modulated by levels of its M2 subunit (RRM2). Here we show that RRM2 overexpression is associated with gemcitabine chemoresistance in pancreatic adenocarcinoma cells, and that suppression of RRM2 expression using RNA interference mediated by small interfering RNA (siRNA) enhances gemcitabine-induced cytotoxicity in vitro. We demonstrate the ability of systemically administered RRM2 siRNA to suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma. Synergism between RRM2 siRNA and gemcitabine results in markedly suppressed tumor growth, increased tumor apoptosis and inhibition of metastasis. Our findings confirm the importance of RRM2 in pancreatic adenocarcinoma gemcitabine chemoresistance. This is the first demonstration that systemic delivery of siRNA-based therapy can enhance the efficacy of an anticancer nucleoside analog.
Recent findings indicate that the expression of the beta-catalytic subunit of the mitochondrial H+-ATP synthase (beta-F1-ATPase) is depressed in liver, kidney and colon carcinomas, providing further a bioenergetic signature of cancer that is associated with patient survival. In the present study, we performed an analysis of mitochondrial and glycolytic protein markers in breast, gastric and prostate adenocarcinomas, and in squamous oesophageal and lung carcinomas. The expression of mitochondrial and glycolytic markers varied significantly in these carcinomas, when compared with paired normal tissues, with the exception of prostate cancer. Overall, the relative expression of beta-F1-ATPase was significantly reduced in breast and gastric adenocarcinomas, as well as in squamous oesophageal and lung carcinomas, strongly suggesting that alteration of the bioenergetic function of mitochondria is a hallmark of these types of cancer.
We have performed oligonucleotide array analysis on various murine lung tissues [normal lungs, lung adenomas, and lung adenocarcinomas (ACs)] using Affymetrix U74Av2 GeneChips to examine the complex genetic changes occurring during lung carcinogenesis. Analysis yielded 20 novel genes differentially expressed in both lung adenomas and ACs versus normal lungs, including the tumor suppressor APC2 and the oncogene Ros 1. In addition, 50 genes were found to be differentially expressed in lung adenomas versus lung ACs, including the differentiation factor Hox C6, the oncogene Ets 2, and the Ras nuclear transport factor, nuclear transport factor 2. To understand the potential relationship between genes expressed in murine lung tumors and its relationship to altered gene expression observed during embryogenesis and postnatal development, tissues from embryonic lungs and from lungs of mice up to 4 weeks following birth were examined using Affymetrix U74Av2 GeneChips. From this analysis, approximately 1300 genes were determined to exhibit differential expression in fetal lung versus postnatal lung. When we compared lung adenomas, lung ACs, and normal lung parenchyma, 24 developmentally regulated genes were found aberrantly expressed in lung tumors; these included the cell cycle control factor CDC5, the cellular differentiation factor TEA domain 4, and the proapoptotic factor BNIP 2. Finally, we compared the murine lung tumor gene expression data to the expression of genes in human lung cancer, in order to assess the relevance of murine lung cancer models in the study of human AC formation. When the 17 human lung ACs and six human lung large cell carcinomas were examined, it was found that 13 of the 17 human lung ACs clustered tightly together in a pattern that was different from the remaining four human lung ACs and six large cell carcinomas, which exhibited a different pattern. Interestingly, the mouse lung adenomas appeared similar to 13 clustered ACs, while mouse lung ACs appeared more similar in pattern to the group consisting of four ACs and six large-cell carcinomas (LCCs). Nevertheless, when compared with the combined human ACs, 39 genes with similar expression changes in murine lung tumors and human ACs/LCCs were identified, such as the oncogene-related BCL7B, the cell cycle regulator CDK4, and the proapoptotic Endophilin B1. Overall, we have determined, for the first time, the expression profiles during murine lung tumor progression and have established, at the molecular level, an association between murine lung tumorigenesis and lung development. We have also attempted to compare the expression profiles found in mouse lung cancers and those in human lung ACs.