Oncogenic potential in prostate cancer is modulated in part by alternative use of genes of the pp32 family. This family includes the tumor suppressor pp32, expressed in normal tissue, and the pro-oncogenic genes pp32r1 and pp32r2 that are found principally in neoplastic cells. At the protein level, pp32, pp32r1, and pp32r2 are approximately 90% identical, yet they subsume opposite functions. In this study, we identify the region of pp32 associated with the ability to inhibit oncogenemediated transformation in a rat embryo fibroblast system, an in vitro correlate of tumor-suppressive activity. Deletion and truncation analysis define a region spanning pp32 amino acids 150 -174 as absolutely required for inhibition of transformed foci elicited by RAS and MYC. Comparison of pp32 with the pp32r1 sequence by moving averages of sequence identity reveals divergence over this region; pp32r2 also differs in this region through truncation after pp32 amino acid 131. The deletion experiments and the experiments of nature therefore converge to demonstrate that tumor-suppressive functions of pp32 reside in amino acids 150 -174. Identification of this minimal tumor-suppressive region should help elaborate the pathways and mechanisms through which pp32 family members exert their functions.pp32 is a member of a closely related family of nuclear phosphoproteins that are alternatively expressed in normal tissues and in human prostate cancer (1-6). Whereas pp32 is a tumor suppressor that is expressed in stem-like and long-lived cells in normal tissues in vivo, pp32r1 and pp32r2 are tumorigenic molecules that are expressed in prostate and breast cancers immediately adjacent to normal tissues that continue to express pp32. The pronounced difference in function of these molecules is striking in view of the high degree of structural conservation. pp32r1 is a 234 amino acid protein that is 87.6% identical to the 249 amino acid pp32; pp32r2, although Cterminally truncated after amino acid 131, is 89.3% identical to pp32 over the length of the predicted protein sequence. Since pp32 inhibits transformation in vitro and tumorigenesis in vivo (1-6), it is reasonable to hypothesize that these functions will map to one or more discrete regions of the pp32 molecule and that pp32 will differ in sequence from pp32r1 and pp32r2 in regions that relate to its tumor suppressor function. In this paper, we localize the pp32 function of inhibition of transformation in vitro and analyze the resultant information in the context of the tumor-derived pp32r1 and pp32r2 sequences. MATERIALS AND METHODS Molecular Biology Reagents and Generation of ExpressionConstructs-All reagents were purchased from Life Technologies, Inc. except for calf intestinal alkaline phosphatase, which was purchased from Roche Molecular Biochemicals. pp32 truncation constructs were generated via polymerase chain reaction amplification of desired pp32 sequences. All constructs utilized a common upstream primer designed to include the 5Ј-untranslated region from base 32 onward, including...
In Egyptian patients with bladder cancer, serum IL-8 is significantly elevated and its level is related to tumor invasion and associated schistosomal infection. Moreover, serum IGF-1 level does not help as a serum tumor marker in these patients.
Hepatocellular carcinoma (HCC) incidence is fast-growing especially in countries highly prevalent with viral hepatitis. Its poor prognosis has driven the research toward the discovery of sensitive markers for early detection. We investigated the usefulness of serum Transforming growth factor-beta1 (TGF-β1), Glypican-3 (GPC3), and Golgi protein-73 (GP73) mRNAs as early biomarkers in HCC Egyptian patients chronically infected with hepatitis C virus (HCV) in comparison with serum alpha-fetoprotein (AFP). Using semi-quantitative RT-PCR and densitometry analysis, circulating TGF-β1, GPC3, and GP73 mRNAs expressions were estimated in 15 healthy adults, 15 chronic HCV (CHC) patients and 25 HCC patients. Serum GP73 expression percentage in HCC group was significantly higher than controls (100 vs. 40 %, P ≤ 0.001) and when compared to elevated serum AFP levels (100 vs. 36 %, P ≤ 0.001). TGF-β1 and GP73 expression means were also higher in HCC patients than controls and CHC patients (P < 0.05). GPC3 expression showed higher frequency in CHC patients compared to HCC group (80 vs. 28 %, P = 0.0016). According to the study cutoffs, serum TGF-β1 and GP73 mRNAs showed 60 and 96 % sensitivities for HCC diagnosis with 100 and 95 % specificities, respectively. Furthermore, elevated GP73 mRNA expression levels in early HCC were significantly increased compared to those of TGF-β1 mRNA and to high serum AFP (92.3 vs. 53.8 and 23.1 %; P = 0.03 and 0.0004, respectively). In conclusion, circulating TGF-β1 and GP73 mRNAs could be useful biomarkers for HCV-induced HCC diagnosis. Moreover, serum GP73 mRNA is sensitive for early cancer detection than AFP and TGF-β1 mRNA. However, these results need further validation studies.
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