Michael Markey, Ph.D. (Advisor); Weiwen Long, Ph.D. (Committee Member); Michael Craig, Ph.D. (Committee Member)
Master of Science (MS)
Melanoma is a potentially lethal type of skin cancer and regarded to be the third most common type of skin cancer. Although melanoma is not as common as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), it is more likely to metastasize than BCC and SCC. Interestingly, the incidence of melanoma continues to go up (expected 2% in 2020), but the deaths continue to decrease (-5.3% in 2020) due to improvements in detection and treatment. The treatment of melanoma depends on several aspects but most importantly the tumor's stage and the location. In the early stages, melanoma can be removed via surgical operation, but in the late stages, melanoma usually treated with radiation or targeted therapy. Many factors predict the development of melanoma like skin pigmentation, age, sun exposure (UV light), and genetic mutations. The p53 protein initiates apoptosis and cell cycle arrest in response to stresses that cause DNA damage like UV light. However, mutant p53 is frequently detected in numerous cancers, including melanoma. MDM2 and MDM4 negatively regulate p53. Notably, a study indicates that MDM4 is overexpressed in 65% of melanoma. Therefore, there is a strong rationale to target MDM4 therapeutically, but MDM4 has several spliced variants, and some variants were detected in human and murine cancers. Yet, no studies have assessed the relative levels of MDM4 splice variants in melanoma. Therefore, in this study, we aimed to identify which variants are expressed in melanoma. We collected clinical specimens and designed specific primers for each isoform by RT-PCR. We observed no expression of MDM4-211 in either malignant and nevi samples. MDM4-Alt1 was present only once in nevi samples. Other variants were similarly present in nevi and malignant samples, but MDM4-A was the most commonly expressed variant in melanoma samples. Data were also collected and analyzed from publicly available databases to examine MDM4 expression in normal skin and melanoma and the survival data associated with each isoform. The results also showed that MDM4-A is the most common isoform expressed in melanoma. In conclusion, our data suggest that aberrant splicing of MDM4 occurs early in carcinogenesis of melanoma, MDM4 is more frequently amplified than its family member MDM2, that MDM4 has more change in splicing than what is observed in MDM2, and supports the view that MDM4-A is an oncogenic variant that promotes carcinogenesis in melanoma.
Year Degree Awarded
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