ABSTRACT
l-type amino acid transporters (LAT1-4) are expressed in various cancer types and are involved in the uptake of essential amino acids such as leucine. Here we investigated the expression of LAT1-4 in endometrial adenocarcinoma and evaluated the contribution of LATs to endometrial cancer cell growth. Analysis of human gene expression data showed that all four LAT family members are expressed in endometrial adenocarcinomas. LAT1 was the most highly expressed, and showed a significant increase in both serous and endometrioid subtypes compared to normal endometrium. Endometrioid patients with the highest LAT1 levels exhibited the lowest disease-free survival. The pan-LAT inhibitor BCH led to a significant decrease in cell growth and spheroid area in four endometrial cancer cell lines tested in vitro. Knockdown of LAT1 by shRNA inhibited cell growth in HEC1A and Ishikawa cells, as well as inhibiting spheroid area in HEC1A cells. These data show that LAT1 plays an important role in regulating the uptake of essential amino acids such as leucine into endometrial cancer cells. Increased ability of BCH compared to LAT1 shRNA at inhibiting Ishikawa spheroid area suggests that other LAT family members may also contribute to cell growth. LAT1 inhibition may offer an effective therapeutic strategy in endometrial cancer patients whose tumours exhibit high LAT1 expression.
Subject(s)
Carcinoma, Endometrioid/metabolism , Carcinoma, Endometrioid/therapy , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/therapy , Large Neutral Amino Acid-Transporter 1/biosynthesis , Amino Acids, Cyclic/pharmacology , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Female , Gene Knockdown Techniques , Humans , Large Neutral Amino Acid-Transporter 1/genetics , Molecular Targeted Therapy , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Spheroids, CellularSubject(s)
Bile Duct Neoplasms/diagnosis , Cholangiocarcinoma/diagnosis , Cholangitis, Sclerosing/diagnosis , Immunoglobulin G/immunology , Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic , Biopsy, Needle , Cholangiocarcinoma/surgery , Cholangiopancreatography, Endoscopic Retrograde/methods , Cholangitis, Sclerosing/surgery , Decompression, Surgical/methods , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Immunohistochemistry , Jaundice, Obstructive/diagnosis , Jaundice, Obstructive/etiology , Laparoscopy/methods , Magnetic Resonance Imaging/methods , Middle Aged , Tomography, X-Ray Computed/methods , Treatment Outcome , Ultrasonography, DopplerABSTRACT
Human papillomavirus (HPV) is a highly transmissible infection responsible for a range of diseases in women including cervical carcinomas, vulval carcinomas, anogenital carcinomas and genital warts. In men it is associated with penile carcinomas, anogenital carcinomas and oropharyngeal carcinomas. The history of the development of HPV vaccines includes a significant Australian input and represents a tremendous advancement in our understanding of HPV virology as well as further elucidating the overall contribution of viruses to carcinogenesis. Prophylactic HPV vaccines were licensed for use in Australia in 2007 in order to protect against development of future cases of cervical carcinoma and early results are promising. The benefit of the vaccine will not be restricted to cervical lesions and cross protection amongst a variety of HPV subtypes is described. The development of the HPV vaccine and its ultimate incorporation into our National Immunisation Schedule is reviewed.
