ALA Photodynamic Therapy, Tumor Hypoxia, CSE1L Phosphorylation, and the Progression and Treatment of Skin Cancer

The incidences of skin cancers continue increasing. Usually there is no sign of pain in early skin cancer, this caused the disease be ignored and rendering the malignant progression of the cancer. The diagnoses of skin cancer are mainly based on skin biopsies. The prognoses of the disease and treatment strategy determination are based on the size, depth, location, invasiveness, and metastasis of tumor. It is essential to develop reliable biomarker that can improve the diagnosis and prognosis of skin cancer to create better outcomes of the patients. Tumor cells often have overexpressed kinase activities and have increased protein phosphorylation level. The CSE1L gene is overexpressed in most cancers including skin cancer and plays an important role in cancer progression. CSE1L is also a phosphorylated protein. There is no commercial anti-phosphorylated CSE1L antibody available. We have produced antibody against phosphorylated CSE1L. In this three year project, we will use the antibody to study the expression of phosphorylated CSE1L in skin cancer including basal cell carcinoma, squamous cell cancer, and melanoma. The clinical-pathological correlation such as TNM stage will be analyzed and the expression of non-phosphorylated CSE1L will also be analyzed for comparison to study the role of phosphorylated CSE1L in the malignant progression of skin cancer. CSE1L is also named as CAS (Cellular Apoptosis Susceptibility) protein, and play an important role in chemotherapeutic drugs induced apoptosis of cancer cells. Topical 5-Aminolevulinic Acid (ALA) laser photodynamic therapy is a common method in skin cancer treatment. CSE1L is over-expressed in various cancers including skin cancer; this project will also study the role of CSE1L in ALA photodynamic therapy induced apoptosis of skin cancer. We will also study whether mixing chemotherapeutic drugs with ALA to increase skin cancer apoptosis induced by CSE1L can increase the efficacy of ALA photodynamic therapy of skin cancer. Hypoxia is a common feature in cancers and plays an important role in cancer metastasis. HIF-1 (hypoxia-inducible factor) activates hypoxia-related proteins and induces cell invasion, angiogenesis, epithelial-mesenchymal transformation, and leading to cancer metastasis. Thus, cellular HIF-1 is a target of cancer drug. Protein kinase activation and protein phosphorylation are crucial in cancer progression. Tumor hypoxia also induces the activation of many protein kinases including Erk1/2 (extracellular-signal-regulated kinases) to transmit tumor progression signals. CSE1L phosphorylation is also regulated by Erk1/2. Thus, there is a possible correlation of CSE1L phosphorylation and tumor progression induced by hypoxia. This project will also use skin cancer cell lines as models and anti-phosphorylated CSE1L antibody to study the relation of hypoxia-related molecules such as Erk1/2, HIF1-alpha, HIF1-beta, pVHL, VEGF, NOS, and CSE1L phosphorylation in the progression of skin cancer. Our preliminary findings have showed that CSE1L secretion and distributed around tumor. Thus, CSE1L may be a target of cancer drugs. The identification of the involvement of CSE1L in cancer invasion and metastasis induced by tumor hypoxia will lead to the development of new drugs for the prevention of skin cancer and the inhibition of cancer metastasis induced by tumor hypoxia to improve the control and treatment of cancer including skin cancer.