| 1. |
- Hedberg, Ylva, 1975-
(författare)
-
Cell Cycle Regulation in Human Renal Cell Carcinoma
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACTCell cycle regulation in human renal cell carcinomaYlva Hedberg, Departments of Medical Biosciences, Pathology, and Surgical andPerioperative Sciences, Urology Andrology, Umeå University, SwedenDeregulated growth control is a hallmark of neoplasia potentially caused by aberrant expression of cell cycle regulatory proteins. The importance of such aberrations in human renal cell carcinoma (RCC) has not been fully clarified. Therefore, the protein expressions of several G1/S regulatory proteins in human RCC were evaluated and their relation to clinico-pathological data was examined.Western blotting and immunohistochemistry were used to detect the proteinexpression of cyclin D1, D3, and E in 80 RCCs. Most tumors expressed higher levels of cyclin D1 (75%) and cyclin E (65%) compared to corresponding normal kidney cortex. In contrast, only 16 % of the tumors had high levels of cyclin D3. In conventional RCCs, low levels of cyclin D1 were associated with large tumor size, aneuploidy and a poor outcome for the patients. High expression of cyclin D3 and Ewere associated with aneuploidy, high proliferation, high TNM-stage, and high nuclear grade. Cyclin E was positively correlated to cyclin D3 but inversely associated with cyclin D1. Cyclin D3 and E were not associated with survival. The majority of RCCs had normal p27 levels, determined by immunohistochemistry, whereas the few tumors with low p27 levels were associated with large tumor size and poor survival.In order to confirm and extend our initial studies, a tissue microarray consisting of 218 RCCs was constructed and cyclin D1, D3, E, p27 were detected by immunohistochemistry. The tissue microarray results were validated by comparing the array data with western analyzes. Due to the large number of tumors analyzed we could evaluate potential differences in expression patterns of cell cycle regulators between conventional, papillary, and chromophobe RCCs. Interestingly, the protein expression differed between RCC types, showing that the conventional tumors generally had high cyclin D1 expression. In contrast, papillary and chromophobe RCCs had high cyclin E expression. Downregulation of p27 was found mostly in chromophobe RCCs. The retinoblastoma protein (pRb) was detected in all RCCs. Phosphorylation of pRb, detected by western blotting or immunohistochemistry and phospho-specific antibodies, was observed in approximately 50% of the tumors. The cdk-inhibitor p16 was not overexpressed suggesting that pRb was functional in the majority of RCCs.In summary, abnormal expression of G1-cyclins and the CDK-inhibitor p27 was common in RCC whereas the main G1/S-substrate, pRb, seemed to be functional. The aberrations further differed between the separate RCC subtypes and were linked to clinical behavior.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Martuszewska, Danuta, et al.
(författare)
-
Tensin3 is a negative regulator of cell migration and all four Tensin family members are downregulated in human kidney cancer.
- 2009
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:2
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Tensin family of intracellular proteins (Tensin1, -2, -3 and -4) are thought to act as links between the extracellular matrix and the cytoskeleton, and thereby mediate signaling for cell shape and motility. Dysregulation of Tensin expression has previously been implicated in human cancer. Here, we have for the first time evaluated the significance of all four Tensins in a study of human renal cell carcinoma (RCC), as well as probed the biological function of Tensin3. PRINCIPAL FINDINGS: Expression of Tensin2 and Tensin3 at mRNA and protein levels was largely absent in a panel of diverse human cancer cell lines. Quantitative RT-PCR analysis revealed mRNA expression of all four Tensin genes to be significantly downregulated in human kidney tumors (50-100% reduction versus normal kidney cortex; P<0.001). Furthermore, the mRNA expressions of Tensins mostly correlated positively with each other and negatively with tumor grade, but not tumor size. Immunohistochemical analysis revealed Tensin3 to be present in the cytoplasm of tubular epithelium in normal human kidney sections, whilst expression was weaker or absent in 41% of kidney tumors. A subset of tumor sections showed a preferential plasma membrane expression of Tensin3, which in clear cell RCC patients was correlated with longer survival. Stable expression of Tensin3 in HEK 293 cells markedly inhibited both cell migration and matrix invasion, a function independent of putative phosphatase activity in Tensin3. Conversely, siRNA knockdown of endogenous Tensin3 in human cancer cells significantly increased their migration. CONCLUSIONS: Our findings indicate that the Tensins may represent a novel group of metastasis suppressors in the kidney, the loss of which leads to greater tumor cell motility and consequent metastasis. Moreover, tumorigenesis in the human kidney may be facilitated by a general downregulation of Tensins. Therefore, anti-metastatic therapies may benefit from restoring or preserving Tensin expression in primary tumors.
|
|
