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Transdifferentiation-inducing HCCR-1 oncogene.

Ha SA, Kim HK, Yoo J, Kim S, Shin SM, Lee YS, Hur SY, Kim YW, Kim TE, Chung YJ, Jeun SS, Kim DW, Park YG, Kim J, Shin SY, Lee YH, Kim JW - BMC Cell Biol. (2010)

Bottom Line: This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis.Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney.Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Genetic Laboratory, Catholic Medical Research Institute, The Catholic University of Korea, Seoul, Korea.

ABSTRACT

Background: Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules.

Results: We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell.

Conclusions: Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

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HCCR-1 is ivolved in tumorigenic conversion and transdifferentiation. Phase-contrast features of wild-type 293 cells (A), cells transfected vector alone (B) and HCCR-1-transfected human 293 cells (C). D. HCCR-1 mRNA expressions in HCCR-1-transfected human 293 cells (designated as clone A, B, C, D, and E, consecutively), and wild-type human 293 cells. E. Hematoxylin-eosin (H-E) staining of tumor nodules taken from the nude mice xenograft. The tumor cells show similar histological features with HCCR-1-transfected allografts. Tumor cells are arranged in nests separated by fine fibrovascular septae and have polygonal shape with oval nuclei, coarse chromatin and moderate amount of cytoplasm. Numerous mitotic figures are found. Immunohistochemical stainings of HCCR-1-transfected human 293 cells xenograft. Tumor cells show positive cytoplasmic stainings for cytokeratin 8 (F), cytokeratin 19 (G), and vimentin (H), respectively. Magnifications, E) × 300; F-H) × 250. Tumorigenic conversion and transdifferentiation of NIH/3T3 cells after transfection with HCCR-1. I and J. H-E staining of tumor nodules taken from nude mice after 3 weeks injection with HCCR-1-transfected NIH/3T3 cells. [I, tumor sections show malignant spindle cell sarcoma; J, tumor sections show poorly differentiated sarcoma with focal epithelial differentiation (arrows)]. Magnification × 400. K. Reticulin stain was performed to detect reticulin fibers. Sections from the same tumor nodule were immunohistochemically stained with mouse monoclonal antibodies (DAKO) specific for epithelial membrane antigen (L), cytokeratin 7 (M), cytokeratin 8 (N), cytokeratin 19 (O), cytokeratin 20 (P), and vimentin (Q). DAB was used as the chromogen. After immunostaining, sections were counterstained with hematoxylin. Magnification × 200.
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Figure 1: HCCR-1 is ivolved in tumorigenic conversion and transdifferentiation. Phase-contrast features of wild-type 293 cells (A), cells transfected vector alone (B) and HCCR-1-transfected human 293 cells (C). D. HCCR-1 mRNA expressions in HCCR-1-transfected human 293 cells (designated as clone A, B, C, D, and E, consecutively), and wild-type human 293 cells. E. Hematoxylin-eosin (H-E) staining of tumor nodules taken from the nude mice xenograft. The tumor cells show similar histological features with HCCR-1-transfected allografts. Tumor cells are arranged in nests separated by fine fibrovascular septae and have polygonal shape with oval nuclei, coarse chromatin and moderate amount of cytoplasm. Numerous mitotic figures are found. Immunohistochemical stainings of HCCR-1-transfected human 293 cells xenograft. Tumor cells show positive cytoplasmic stainings for cytokeratin 8 (F), cytokeratin 19 (G), and vimentin (H), respectively. Magnifications, E) × 300; F-H) × 250. Tumorigenic conversion and transdifferentiation of NIH/3T3 cells after transfection with HCCR-1. I and J. H-E staining of tumor nodules taken from nude mice after 3 weeks injection with HCCR-1-transfected NIH/3T3 cells. [I, tumor sections show malignant spindle cell sarcoma; J, tumor sections show poorly differentiated sarcoma with focal epithelial differentiation (arrows)]. Magnification × 400. K. Reticulin stain was performed to detect reticulin fibers. Sections from the same tumor nodule were immunohistochemically stained with mouse monoclonal antibodies (DAKO) specific for epithelial membrane antigen (L), cytokeratin 7 (M), cytokeratin 8 (N), cytokeratin 19 (O), cytokeratin 20 (P), and vimentin (Q). DAB was used as the chromogen. After immunostaining, sections were counterstained with hematoxylin. Magnification × 200.

Mentions: HEK-293 is a short spindle shaped cell having a bipolar cell process (Figure 1A). Cultured 293 cells have similar cytological features to cells transfected with vector alone (Figure 1B). However, HCCR-1-transfected human 293 cells showed increase in cell size compared to wild-type human 293 cells (Figure 1C). The cell processes were blunted in HCCR-1-transfected human 293 cells. Northern blot showed that about 2.0-kilobase-pair mRNA transcript was over-expressed in all five HCCR-1-transfected human 293 cells as compared with wild-type 293 cells (Figure 1D). Nude mice injected with HCCR-1-transfected human 293 cells showed palpable tumors in four weeks. But cells transfected with vector alone did not induce tumor formation in nude mice. Sections of the nude mice tumor nodules bearing HCCR-1-transfected human 293 cells revealed epithelial cell carcinomas (Figure 1E). Interestingly, however, the cells showed co-expression of epithelial markers, such as cytokeratin 8 (Figure 1F) and cytokeratin 19 (Figure 1G), and of the mesenchymal marker, vimentin that is normally expressed by fibroblasts (Figure 1H). These results suggest that transdifferentiation (EMT) occurred in HCCR-1 stably transfected 293 cells derived from nude mouse tumors.


Transdifferentiation-inducing HCCR-1 oncogene.

Ha SA, Kim HK, Yoo J, Kim S, Shin SM, Lee YS, Hur SY, Kim YW, Kim TE, Chung YJ, Jeun SS, Kim DW, Park YG, Kim J, Shin SY, Lee YH, Kim JW - BMC Cell Biol. (2010)

HCCR-1 is ivolved in tumorigenic conversion and transdifferentiation. Phase-contrast features of wild-type 293 cells (A), cells transfected vector alone (B) and HCCR-1-transfected human 293 cells (C). D. HCCR-1 mRNA expressions in HCCR-1-transfected human 293 cells (designated as clone A, B, C, D, and E, consecutively), and wild-type human 293 cells. E. Hematoxylin-eosin (H-E) staining of tumor nodules taken from the nude mice xenograft. The tumor cells show similar histological features with HCCR-1-transfected allografts. Tumor cells are arranged in nests separated by fine fibrovascular septae and have polygonal shape with oval nuclei, coarse chromatin and moderate amount of cytoplasm. Numerous mitotic figures are found. Immunohistochemical stainings of HCCR-1-transfected human 293 cells xenograft. Tumor cells show positive cytoplasmic stainings for cytokeratin 8 (F), cytokeratin 19 (G), and vimentin (H), respectively. Magnifications, E) × 300; F-H) × 250. Tumorigenic conversion and transdifferentiation of NIH/3T3 cells after transfection with HCCR-1. I and J. H-E staining of tumor nodules taken from nude mice after 3 weeks injection with HCCR-1-transfected NIH/3T3 cells. [I, tumor sections show malignant spindle cell sarcoma; J, tumor sections show poorly differentiated sarcoma with focal epithelial differentiation (arrows)]. Magnification × 400. K. Reticulin stain was performed to detect reticulin fibers. Sections from the same tumor nodule were immunohistochemically stained with mouse monoclonal antibodies (DAKO) specific for epithelial membrane antigen (L), cytokeratin 7 (M), cytokeratin 8 (N), cytokeratin 19 (O), cytokeratin 20 (P), and vimentin (Q). DAB was used as the chromogen. After immunostaining, sections were counterstained with hematoxylin. Magnification × 200.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: HCCR-1 is ivolved in tumorigenic conversion and transdifferentiation. Phase-contrast features of wild-type 293 cells (A), cells transfected vector alone (B) and HCCR-1-transfected human 293 cells (C). D. HCCR-1 mRNA expressions in HCCR-1-transfected human 293 cells (designated as clone A, B, C, D, and E, consecutively), and wild-type human 293 cells. E. Hematoxylin-eosin (H-E) staining of tumor nodules taken from the nude mice xenograft. The tumor cells show similar histological features with HCCR-1-transfected allografts. Tumor cells are arranged in nests separated by fine fibrovascular septae and have polygonal shape with oval nuclei, coarse chromatin and moderate amount of cytoplasm. Numerous mitotic figures are found. Immunohistochemical stainings of HCCR-1-transfected human 293 cells xenograft. Tumor cells show positive cytoplasmic stainings for cytokeratin 8 (F), cytokeratin 19 (G), and vimentin (H), respectively. Magnifications, E) × 300; F-H) × 250. Tumorigenic conversion and transdifferentiation of NIH/3T3 cells after transfection with HCCR-1. I and J. H-E staining of tumor nodules taken from nude mice after 3 weeks injection with HCCR-1-transfected NIH/3T3 cells. [I, tumor sections show malignant spindle cell sarcoma; J, tumor sections show poorly differentiated sarcoma with focal epithelial differentiation (arrows)]. Magnification × 400. K. Reticulin stain was performed to detect reticulin fibers. Sections from the same tumor nodule were immunohistochemically stained with mouse monoclonal antibodies (DAKO) specific for epithelial membrane antigen (L), cytokeratin 7 (M), cytokeratin 8 (N), cytokeratin 19 (O), cytokeratin 20 (P), and vimentin (Q). DAB was used as the chromogen. After immunostaining, sections were counterstained with hematoxylin. Magnification × 200.
Mentions: HEK-293 is a short spindle shaped cell having a bipolar cell process (Figure 1A). Cultured 293 cells have similar cytological features to cells transfected with vector alone (Figure 1B). However, HCCR-1-transfected human 293 cells showed increase in cell size compared to wild-type human 293 cells (Figure 1C). The cell processes were blunted in HCCR-1-transfected human 293 cells. Northern blot showed that about 2.0-kilobase-pair mRNA transcript was over-expressed in all five HCCR-1-transfected human 293 cells as compared with wild-type 293 cells (Figure 1D). Nude mice injected with HCCR-1-transfected human 293 cells showed palpable tumors in four weeks. But cells transfected with vector alone did not induce tumor formation in nude mice. Sections of the nude mice tumor nodules bearing HCCR-1-transfected human 293 cells revealed epithelial cell carcinomas (Figure 1E). Interestingly, however, the cells showed co-expression of epithelial markers, such as cytokeratin 8 (Figure 1F) and cytokeratin 19 (Figure 1G), and of the mesenchymal marker, vimentin that is normally expressed by fibroblasts (Figure 1H). These results suggest that transdifferentiation (EMT) occurred in HCCR-1 stably transfected 293 cells derived from nude mouse tumors.

Bottom Line: This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis.Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney.Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Genetic Laboratory, Catholic Medical Research Institute, The Catholic University of Korea, Seoul, Korea.

ABSTRACT

Background: Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules.

Results: We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell.

Conclusions: Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

Show MeSH
Related in: MedlinePlus