Synchronous High-Grade Squamous Intraepithelial Lesion of the Fimbria of the Fallopian Tube in a 51-Year-Old Woman with Invasive Squamous Cell Carcinoma of the Uterine Cervix.

Primary squamous cell carcinoma or squamous intraepithelial lesion of the fallopian tube is a very rare finding with only a small number of cases worldwide. We describe the case of a 51-year-old woman, undergoing an abdominal hysterectomy after the diagnosis of an HPV-associated invasive squamous cell carcinoma of the uterine cervix with the unexpected detection of an HPV16-positive high-grade squamous intraepithelial lesion of the fimbria of the right fallopian tube in the resection specimen. The finding of an isolated, HPV-associated squamous intraepithelial lesion in the fallopian tube raises the question of a de novo development in this body compartment (after exclusion of a continuous metastatic spread from the uterine cervix) by taking a virus-associated field effect into account and should encourage the inclusion of this possibility when examining the fallopian tube in a routine setting.

Embryonic lethal abnormal vision-like HuR-dependent mRNA stability regulates post-transcriptional expression of cyclin-dependent kinase inhibitor p27Kip1.

The cyclin-dependent kinase inhibitor p27(Kip1) plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27(Kip1) expression is of significant interest. The embryonic lethal abnormal vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27(Kip1), however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27(Kip1) mRNA. Specifically, human and mouse p27(Kip1) mRNAs interact with HuR protein through multiple U-rich elements in both 5' and 3' untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27(Kip1) mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27(Kip1) mRNA and reduces its accumulation. We also identified a CT repeat in the 5' UTR of full-length p27(Kip1) mRNA isoforms that interact with a approximately 41-kDa protein and represses p27(Kip1) expression. This CT-rich element and diffuse elements in the 3' UTR regulate post-transcriptional expression of p27(Kip1) at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27(Kip1) expression.

Dual role of carcinoembryonic antigen-related cell adhesion molecule 1 in angiogenesis and invasion of human urinary bladder cancer.

Here, we show that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in umbrella cells of bladder urothelium but is down-regulated in superficial bladder cancer, such as histologic tumor stage a (pTa) and transitional cell carcinoma in situ (pTis). Concurrently, CEACAM1 is up-regulated in the endothelia of adjacent angiogenic blood vessels. Mimicking the CEACAM1 down-regulation in the urothelium, CEACAM1 was silenced in bladder cancer cell lines 486p and RT4 using the small interfering RNA technique. CEACAM1 down-regulation was confirmed at the protein level by Western blot analyses. CEACAM1 silencing leads to a significant up-regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D in quantitative reverse transcription-PCR. Correspondingly, supernatants from the CEACAM1-overexpressing bladder cancer cell lines reduce, but those from CEACAM1 silencing induce endothelial tube formation and potentiate the morphogenetic effects of VEGF. These data suggest that the epithelial down-regulation of CEACAM1 induces angiogenesis via increased expression of VEGF-C and VEGF-D. Inversely, CEACAM1 is up-regulated in endothelial cells of angiogenic blood vessels. This in turn is involved in the switch from noninvasive and nonvascularized to invasive and vascularized bladder cancer. CEACAM1 appears to be a promising endothelial target for bladder cancer therapy.