Discussion

In this report, we demonstrated the expression patterns of ERRs in various human prostatic epithelial cell lines, CWR22 xenografts and prostatic tissues. Among the three ERR isoforms, ERRa transcripts were expressed in all tested cell lines, CWR22 xenografts and human prostatic tissues, whereas ERRP and ERRy showed variable expression patterns. Immunohistochemistry of demonstrated that immunoreacted proteins were mainly localized to the glandular epithelia of normal prostate. The wide expression of in prostatic cell lines and xenografts suggests that expression could be important to the prostatic cells. An examination of its relative expression levels as shown by RT-PCR in different cell lines shows that ERRa is expressed at higher levels in the four normal immortalized cell lines and an immortalized primary prostatic carcinoma cell line, CA-HPV-10, and at lower levels in four cancer cell lines, which are established from prostatic carcinoma metastasized to secondary sites. Its expression level was low in two androgen-independent lines, DU 145 and PC-3. Furthermore, RT-PCR of ERRa showed a similar expression pattern in prostatic tissues that ERRa was expressed at higher levels in hyperplastic tissues than in neoplastic tissues, suggesting that ERRa could be down-regulated in the progression of prostate cancer. It is also noted that transcripts were expressed at high levels in two androgen-independent and bone metastatic prostatic cancer cells, MDA PCa 2b and C4-2B. MDA PCa 2b was established from an androgen-independent bone metastatic prostate cancer patient, whereas C4-2B was derived from LNCaP cells in metastatic lesions in lumbar spine of castrated nude mice, both of which express androgen receptor. However, its expression was low in another bone metastatic and androgen-independent line, PC-3, of which androgen receptor is expressed at low level.

Compared to and showed weak expression in four normal immortalized cell lines and MDA PCa 2b, and barely detected in LNCaP, PC-3 and CWR22R xenografts, but negative in other lines, suggesting that its expression is down-regulated in tumor progression but transcribed in bone metastastic cells. It is uncertain whether the expression of ERRa and ERRp in two bone metastatic lines, MDA PCa 2 b and PC-3, is related to bone metastasis of prostate cancer.

On the other hand, ERRy is weakly expressed in the four normal immortalized cell lines and undetected in three androgen-independent lines, CWR22Rvl, DU 145 and MDA PCa 2b. High expression level of ERRy was detected in two CWR22 xenografts, C4-2B and PC-3. Its variable expression in different prostatic cancer cell lines reflects the clonal and genetic heterogeneity of the tumors.

Since ERRs are closely related to ERs, we also examined and compared their mRNA expression patterns in prostatic cells. We observed that ERP was positively expressed in all tested cell lines and xenografts, and exhibited a similar expression pattern as that of ERRa. Similarly, ERa showed a similar expression pattern as that of ERRy in the tested cell lines. The results suggest that members of both nuclear receptors, which are different in their ligand dependence, are co-expressed in the prostatic cells and they could crosstalk between one another or share similar regulatory pathways through competition for DNA binding sites and coregulatory proteins. However, the regulatory roles ofERRs in prostatic cells are still unclear and require further studies.

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