Carcinogenesis

About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.

Host cyclooxygenase-2 modulates carcinoma growth

Abstract: Cyclooxygenase-2 (COX-2; Ptgs2) acts as a tumor promoter in rodent models for colorectal cancer, but its precise role in carcinogenesis remains unclear. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacological approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid tumors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2(-/-), but not COX-1(-/-) or wild-type mice. Treatment of wild-type C57BL/6 mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2(-/-) mice when compared with those in wild-type mice. Because COX-2 is expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2(-/-) mouse fibroblasts and found a 94% reduction in their ability to produce the proangiogenic factor, VEGF. Additionally, treatment of wild-type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%.

p53 inhibition by the LANA protein of KSHV protects against cell death.

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B-cell lymphoproliferative diseases1,2,3. Most cells in lesions derived from these malignancies are latently infected, and different viral gene products have been identified in association with lytic or latent infection by KSHV4,5. The latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a highly immunogenic protein that is expressed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas6,7. Antibodies to LANA can be detected in a high percentage of HIV-infected individuals who subsequently develop KS8,9, although its role in disease pathogenesis is not completely understood. p53 is a potent transcriptional regulator of cell growth whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis10,11, and several viral oncoproteins interact with p53 and modulate its biological activity12,13. Here we show that LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity. This viral gene product further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function.

Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis.

Abstract: Oncogenic transformation by human adenoviruses requires early regions 1A and 1B (E1A and E1B) and provides a model of multistep carcinogenesis. This study shows that the metabolic stabilization of p53 observed in adenovirus 5 (Ad5)-transformed cells can occur in untransformed cells expressing E1A alone. Stabilized p53 was localized to the nucleus and was indistinguishable from wild-type p53 with respect to its interactions with hsc70, PAb420, Ad5 p55E1B, and SV40 large T antigen. Moreover, binding of Ad5 p55E1B or SV40 large T antigen had no additional effect on p53 levels or turnover. Higher levels of p53 were also induced in a variety of cell types within 40 hr after transferring E1A genes. E1A also caused cells to lose viability by a process resembling apoptosis. The apoptosis appeared to involve p53, because p53 levels reverted to normal in surviving cells that had lost E1A, and E1B protected cells from the toxic effects of E1A. These results suggest that (1) the involvement of p53 in tumor suppression and/or apoptosis can be regulated at the level of protein turnover, and (2) a major oncogenic role for E1B is to counter cellular responses to E1A (i.e., stabilization of p53 and associated apoptosis) that preclude transformation by E1A alone. This represents the first physiological setting in which high levels of endogenous p53 are induced in response to an oncogenic challenge, with the apparent consequence of suppressing transformation.

MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene.

Abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively control expression of target genes in animals and plants. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly overexpressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. We initiated a screen to identify miR-21 target genes using a reporter assay and identified a potential miR-21 target in the 3'-UTR of the programmed cell death 4 (PDCD4) gene. We cloned the full-length 3'-UTR of human PDCD4 downstream of a reporter and found that mir-21 downregulated, whereas a modified antisense RNA to miR-21 upregulated reporter activity. Moreover, deletion of the putative miR-21-binding site (miRNA regulatory element, MRE) from the 3'-UTR of PDCD4, or mutations in the MRE abolished the ability of miR-21 to inhibit reporter activity, indicating that this MRE is a critical regulatory region. Western blotting showed that Pdcd4 protein levels were reduced by miR-21 in human and mouse cells, whereas quantitative real-time PCR revealed little difference at the mRNA level, suggesting translational regulation. Finally, overexpression of mir-21 in MCF-7 human breast cancer cells and mouse epidermal JB6 cells promoted soft agar colony formation by downregulating Pdcd4 protein levels. The demonstration that miR-21 promotes cell transformation supports the concept that mir-21 functions as an oncogene by a mechanism that involves translational repression of the tumor suppressor Pdcd4.