Abstract 69P
Background
Hippo pathway consists of a kinase cascade and regulatory components, whose aberrant expression contributes to oncogenesis. Uveal melanoma (UM) is a treatment-resistant intraocular malignancy in adults, with limited therapeutic options and high metastasis rates. Oncogenomic analyses of UM tumors revealed widespread genomic alterations of GNAQ/11 gene affecting multiple pathways. Hippo pathway appears to play a major role in regulating tumor progression and may represent a promising target for novel therapies in UM. Therefore, we elucidate the differential expression of Hippo pathway kinases and their association with high-risk clinicopathological parameters and their impact on the prognosis of UM patients.
Methods
Quantitative Real-Time PCR (qRT-PCR) was used to determine the mRNA expression level of 9 Hippo kinases (MST1, MST2, LATS1, LATS2, SAV1, MOB1A, MOB1B, NDR1 and NDR2,) in 32 prospective UM cases and correlated with clinicopathological parameters along with patient outcome.
Results
Sixty percent patients exhibited advanced tumor staging with a male preponderance (68.7%). High pigmentation and scleral invasion were present in 65.6% and 31.2% cases, respectively. The mRNA expression levels of LATS1, LATS2, SAV1, MOB1A and NDR1 genes were found to be downregulated in more than 50% of cases, with mean fold changes of 0.38, 1.07, 1.54, 1.39, and 0.77, respectively. Conversely, MST1, MST2, MOB1B and NDR2 were upregulated in more than 50% of cases, with mean fold changes of 2.18, 3.14, 2.09, and 4.09, respectively. Six patients developed distant metastasis of which four died due to the disease.
Conclusions
Our data reveal substantial mRNA-level deregulation of Hippo pathway kinases in UM patients. Downregulation of these kinases contributes to UM aggressiveness. These findings may pave the way for developing predictive biomarkers and therapeutic targets for management and treatment of UM. However, additional investigations are required in understanding the precise mechanisms of Hippo signaling components, and will also help in realizing the potential of therapeutics to modulate central mediators (YAP/TAZ) protein activity and suppressing oncogenesis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Indian Council of Medical Research.
Disclosure
All authors have declared no conflicts of interest.