| Abstract: |
Metastatic prostate cancer (PCa) is one of the leading causes of death from cancer in men. The molecular mechanisms underlying the transition from localized tumor to hormone-refractory metastatic PCa remain largely unknown, and their identification is key for predicting prognosis and targeted therapy. Here we demonstrated that increased expression of a splice variant of the Kruppel-like factor 6 (KLF6) tumor suppressor gene, known as KLF6-SV1, in tumors from men after prostatectomy predicted markedly poorer survival and disease recurrence profiles. Analysis of tumor samples revealed that KLF6-SV1 levels were specifically upregulated in hormone-refractory metastatic PCa. In 2 complementary mouse models of metastatic PCa, KLF6-SV1-overexpressing PCa cells were shown by in vivo and ex vivo bioluminescent imaging to metastasize more rapidly and to disseminate to lymph nodes, bone, and brain more often. Interestingly, while KLF6-SV1 overexpression increased metastasis, it did not affect localized tumor growth. KLF6-SV1 inhibition using RNAi induced spontaneous apoptosis in cultured PCa cell lines and suppressed tumor growth in mice. Together, these findings demonstrate that KLF6-SV1 expression levels in PCa tumors at the time of diagnosis can predict the metastatic behavior of the tumor; thus, KLF-SV1 may represent a novel therapeutic target. |
| Keywords: |
immunohistochemistry; cancer survival; controlled study; human tissue; protein expression; human cell; proto-oncogene proteins; cancer recurrence; postoperative period; nonhuman; treatment duration; bone metastasis; lymph node metastasis; lymphatic metastasis; mouse; animals; mice; animal tissue; gene overexpression; metastasis; apoptosis; tumor volume; animal experiment; animal model; small interfering rna; genetic variability; rna interference; in vivo study; drug effect; mice, scid; cell line, tumor; cancer model; mice, inbred balb c; time factors; carcinogenesis; prostate cancer; prostatic neoplasms; cancer inhibition; gene expression regulation, neoplastic; human cell culture; mice, nude; prostatectomy; disease progression; brain metastasis; neoplasm metastasis; kruppel like factor 6; kruppel-like transcription factors; transplantation, heterologous; upregulation; tumor growth; disease models, animal; ex vivo study; bioluminescence; neoplastic processes
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