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.

p63 and p73: roles in development and tumor formation.

Abstract: The tumor suppressor p53 is critically important in the cellular damage response and is the founding member of a family of proteins. All three genes regulate cell cycle and apoptosis after DNA damage. However, despite a remarkable structural and partly functional similarity among p53, p63, and p73, mouse knockout studies revealed an unexpected functional diversity among them. p63 and p73 knockouts exhibit severe developmental abnormalities but no increased cancer susceptibility, whereas this picture is reversed for p53 knockouts. Neither p63 nor p73 is the target of inactivating mutations in human cancers. Genomic organization is more complex in p63 and p73, largely the result of an alternative internal promoter generating NH2-terminally deleted dominant-negative proteins that engage in inhibitory circuits within the family. Deregulated dominant-negative p73 isoforms might play an active oncogenic role in some human cancers. Moreover, COOH-terminal extensions specific for p63 and p73 enable further unique protein-protein interactions with regulatory pathways involved in development, differentiation, proliferation, and damage response. Thus, p53 family proteins take on functions within a wide biological spectrum stretching from development (p63 and p73), DNA damage response via apoptosis and cell cycle arrest (p53, TAp63, and TAp73), chemosensitivity of tumors (p53 and TAp73), and immortalization and oncogenesis (DeltaNp73).

The APC gene product in normal and tumor cells.

Abstract: The APC gene has been found to be mutated during the development of sporadic colorectal tumors as well as in the germ line of familial adenomatous polyposis patients. To facilitate the characterization of both normal and mutant APC protein, a series of monoclonal and polyclonal antibodies specific for the APC protein was produced. When lymphoblastoid cell lines derived from seven familial adenomatous polyposis patients with known mutations were analyzed by Western blot, an approximately 300-kDa protein corresponding to the predicted size of full-length APC was detected in all 7 cell lines. In addition, truncated APC proteins corresponding to the product of the known mutated alleles could be detected in 4 of the 7 lines. Similar analysis of 23 colon carcinoma and 9 adenoma cell lines revealed truncated proteins in 24 (75%) of the cell lines. Moreover, 26 (81%) of the colon tumor lines were totally devoid of the normal, full-length protein. In contrast, Western blot analysis of 40 cell lines derived from sporadic tumors of other organs detected only full-length APC. Immunohistochemical analysis of APC in normal colonic mucosa revealed cytoplasmic staining with more intense staining in the basolateral margins of the epithelial cell. This staining was markedly increased in the upper portions of the crypts, suggesting an increased level of expression with maturation. These studies provide some initial clues to the function of the cytoplasmic protein APC and demonstrate the feasibility of identifying APC mutations by direct analysis of the APC protein.

Dicer1 functions as a haploinsufficient tumor suppressor

Abstract: MicroRNAs (miRNAs) are short, noncoding RNAs that function to suppress post-transcriptionally the expression of target mRNAs, predominately via inhibition of translation. Such translational inhibition relies on imperfect base-pairing between the miRNA and the target transcript, with the interaction at nucleotides 2–8 (or the “seed” region) of the miRNA being required for translational repression. Computational prediction of miRNA targets based on seed regions and sequence conservation has revealed a widespread potential for miRNA-mediated transcript regulation, with hundreds of putative mRNA targets for an individual miRNA (Bartel 2004). In line with their broad-based effects, miRNAs have been proposed to function as oncogenes or tumor suppressor genes based on their inhibition of a variety of tumor-suppressive and oncogenic mRNAs, respectively (Plasterk 2006; Ventura and Jacks 2009). In particular, three distinct mechanisms have been posited. First, oncogenic miRNAs can undergo gain of function in tumors. This has been most clearly demonstrated for the miR-17∼92 cluster, whose amplification in B-cell lymphomas promotes their development, potentially through its control of B-cell differentiation (He et al. 2005; Koralov et al. 2008; Ventura et al. 2008). Furthermore, tumor-suppressive miRNAs could undergo loss of function in tumors. This has been shown for several miRNAs, including the let-7 family, whose expression can limit lung tumorigenesis through inhibition of oncogenes like the Ras family and HMGA2 (Esquela-Kerscher et al. 2008; Kumar et al. 2008). In particular, let-7 family members are in sites of frequent deletion in human tumors, and their processing is inhibited by the oncogenic Lin-28 proteins (Heo et al. 2008; Newman et al. 2008; Viswanathan et al. 2008; Chang et al. 2009). Finally, oncogenes can acquire mutations to remove miRNA-binding sites in tumors. This has been described for HMGA2, whose translocation promotes lipoma development by releasing the transcript from let-7-mediated tumor suppression (Mayr et al. 2007). We reported a global down-regulation of miRNAs in several types of human and murine cancer (Lu et al. 2005). From this initial study, it was unclear whether this widespread loss of miRNAs was merely a consequence of tumor development or was functionally related to the disease process. We demonstrated previously that this global loss of miRNAs was functionally relevant to oncogenesis, as impairment of miRNA maturation enhanced transformation in both cancer cells and a K-Ras-driven model of lung cancer (Kumar et al. 2007). While these studies provide a framework to explain inhibition of miRNA biogenesis in cancer, the genetic basis of impaired miRNA processing in human cancer has been largely undefined. For a subset of miRNAs, widespread silencing occurs at the transcriptional level via the c-Myc oncogene (Chang et al. 2008). However, it has also been shown that such broad reductions in miRNAs can occur post-transcriptionally, since changes in miRNA levels frequently occur without changes in the levels of the primary miRNA transcript (Thomson et al. 2006). Recently, it was shown that mutations in the miRNA processing component TARBP2 occur frequently in mismatch repair-deficient colon cancer, and that these mutations promote tumorigenesis by impaired processing of miRNAs (Melo et al. 2009). While interesting, these limited cases do not resolve the common global reduction of miRNAs in human cancers. Moreover, the precise genetics of such changes in tumors is poorly defined, especially as no components of the miRNA processing pathway have been reported to be completely deleted in human tumors. This is not surprising, since it has been shown that germline deletion of miRNA processing components Dicer1 and Dgcr8 in mice fails to produce viable progeny (Bernstein et al. 2003; Wang et al. 2007). Thus, conditional deletion of miRNA processing components provides a powerful means of examining the role of miRNAs in tumorigenesis.

The inhibitors of apoptosis: there is more to life than Bcl2.

Abstract: The inhibitor of apoptosis (IAP) genes constitute a highly conserved family found in organisms as diverse as insects and mammals. These genes encode proteins that directly bind and inhibit caspases, and thus play a critical role in deciding cell fate. The IAPs are in turn regulated by endogenous proteins (second mitochondrial activator of caspases and Omi) that are released from the mitochondria during apoptosis. Overexpression of the IAPs, particularly the X-chromosome-linked IAP, has been shown to be protective in a variety of experimental animal models of human neurodegenerative diseases. Furthermore, overexpression of one or more of the IAPs in cancer cell lines and primary tumor samples appears to be a frequent event. IAP gene amplification and translocation events provide genetic evidence that further strengthens the case for classifying the IAPs as oncogenes. Therapeutic strategies that interfere with IAP expression or function are under investigation as an adjuvant to conventional chemotherapy- and radiation-based cancer therapy. This paper reviews the structure and function of the IAP family members and their inhibitors, and surveys the available evidence for IAP dysregulation in cancer.

Role of iron in carcinogenesis: cancer as a ferrotoxic disease.

Abstract: Iron is abundant universally. During the evolutionary processes, humans have selected iron as a carrier of oxygen inside the body. However, iron works as a double-edged sword, and its excess is a risk for cancer, presumably via generation of reactive oxygen species. Thus far, pathological conditions such as hemochromatosis, chronic viral hepatitis B and C, exposure to asbestos fibers, as well as endometriosis have been recognized as iron overload-associated risks for human cancer. Indeed, iron is carcinogenic in animal experiments. These reports unexpectedly revealed that there are target genes in iron-induced carcinogenesis and that iron-catalyzed oxidative DNA damage is not random in vivo. Several iron transporters and hepcidin, a peptide hormone regulating iron metabolism, were discovered in the past decade. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy decreased cancer risk in the apparently normal population. These results warrant reconsideration of the role of iron in carcinogenesis and suggest that fine control of body iron stores would be a wise strategy for cancer prevention.