The conversion of normal cells into tumor cells involves changes in the activity of a number of distinct different genes and proteins in a cell. Although researchers have been able to transform normal mouse cells into tumor-forming cells by introducing several cooperating oncogenes into these cells, human cells have been resistant to such transformation [8
]. In this study, ectopic expression of HCCR-1
alone results in direct tumorigenic conversion of HEK-293 cells in vitro
and in vivo
Because NIH/3T3 cell is of mesenchymal origin [14
],sarcoma would typically develop from oncogene-transformed NIH/3T3 [30
]. But, nude mice bearing HCCR-1
allograft display characteristics of epithelial carcinomas. Because acquisition of epithelial properties by the fibroblast-derived cells mimics the mesenchymal to epithelial conversion of cells during the organogenesis of the kidney [20
], we investigated whether HCCR-1
is expressed in the developing kidney. The developing nephrons in the cortex were not stained. But the basolateral plasma membranes of the developing collecting duct, which are derived from the ureteric bud [21
],were especially reactive to HCCR-1 antibody. Because nephrogenesis is stimulated by a distinct ureteric signal, diffusion-limited basolateral molecules [22
],which trigger mesenchymal to epithelial conversion, we propose that the HCCR-1
product may be a mesenchyme-derived regulatory factor [23
]that stimulates morphogenesis of epithelia in the developmental process and mediates interactions between mesenchyme and epithelia during neoplastic transformation. Our study suggests that overexpression of HCCR-1
induces tumorigenesis, transdifferentiation and embryonic kidney development.
Transdifferentiation is a change from one differentiated phenotype to another involving morphological and functional phenotypic markers [31
]. The conversion of a cell phenotype is likely to be accomplished by selective enhancement of gene expression, which controls the terminal developmental commitment of cells [33
].There is little known about 'master switch' genes that determine a specific differentiation pathway and have the potential to induce the process in a cell originally destined for a different differentiation pathway [31
might play multiple developmental roles by mediating a signal originating from the mesenchyme and received by epithelia. Mesenchymal signals are known to govern differentiation and morphogenesis of many epithelia, but the molecular nature of the signals is poorly understood. This expression pattern indicates that this mesenchymal factor can transmit morphogenetic signals in epithelia development and suggests a molecular mechanisim for mesenchymal epithelial interactions.
There is evidence to indicate that tumors develop secondarily to abnormalities in PKC-mediated signal transduction [34
].Reports show that PKC induces a marked increase in telomerase activity [26
].Besides tumor cells typically have acquired damage to genes that directly regulate their cell cycles [35
]. Our study suggests that deregulation of HCCR-1
activity in mouse NIH/3T3 cells might result in the activation of PKC or telomerase, loss of particular cell cycle checkpoint controls, and downregulation of tumor suppressor egr-1, thereby predisposing NIH/3T3 cells to malignant conversion.
This present study suggests that HCCR-1
is an oncogene which induces the transformation of HEK293 and NIH3T3 cells. Likewise, our previous study also demonstrated that HCCR-1
is a mitochondrial out membrane protein and suppresses the apoptosis [36
]. Consistent with this previous work, this study also reveals the anti-apoptotic activity of HCCR-1
by reducing the expression of Egr-1, a direct regulator of multiple tumor suppressors including TGF beta1, PTEN, and p53. Therefore, both studies support that HCCR-1
is an oncogene either by suppressing apoptotic activities or by dysregulating Egr-1, telomerase, or PKC activity. Since key functions related to apoptosis or anti-apoptosis often occur in mitochondria, it is not too surprising that HCCR-1
localizes to the mitochondria.