New Insights into the Link between Melanoma and Thyroid Cancer: Role of Nucleocytoplasmic Trafficking

Abstract

Cancer remains a major public health concern, mainly because of the incompletely understood dynamics of molecular mechanisms for progression and resistance to treatments. The link between melanoma and thyroid cancer (TC) has been noted in numerous patients. Nucleocytoplasmic transport of oncogenes and tumor suppressor proteins is a common mechanism in melanoma and TC that promotes tumorigenesis and tumor aggressiveness. However, this mechanism remains poorly understood. Papillary TC (PTC) patients have a 1.8-fold higher risk for developing cutaneous malignant melanoma than healthy patients. Our group and others showed that patients with melanoma have a 2.15 to 2.3-fold increased risk of being diagnosed with PTC. The BRAF V600E mutation has been reported as a biological marker for aggressiveness and a potential genetic link between malignant melanoma and TC. The main mechanistic factor in the connection between these two cancer types is the alteration of the RAS-RAF-MEK-ERK signaling pathway activation and translocation. The mechanisms of nucleocytoplasmic trafficking associated with RAS, RAF, and Wnt signaling pathways in melanoma and TC are reviewed. In addition, we discuss the roles of tumor suppressor proteins such as p53, p27, forkhead O transcription factors (FOXO), and NF-_KB within the nuclear and cytoplasmic cellular compartments and their association with tumor aggressiveness. A meticulous English-language literature analysis was performed using the PubMed Central database. Search parameters included articles published up to 2021 with keyword search terms melanoma and thyroid cancer, BRAF mutation, and nucleocytoplasmic transport in cancer.

Keywords: BRAF V600E; melanoma; nucleocytoplasmic transport; resistance; thyroid cancer; tumor aggressiveness.

Figure 1

Risk of second primary thyroid cancer (SPTC) following malignant melanoma. (A) Standardized Incidence Ratio (SIR) stratified according to the gender and age groups. (B) Latency course of risk of SPTC within the first 10 years of follow-up of melanoma patients. The error bars indicate the 95%CI.

Figure 2

Nucleocytoplasmic translocation. (A) Signaling molecules trafficking in the MAPK and WNT signaling pathways in melanoma and thyroid cancer. (B) Example for the transport cycle of importins. Import of NLS-containing cargos is mediated by importin αβ. Importin α recognizes and binds the NLS of the cargo as well as importin β. After transport through the nuclear pore channels (NPC), the GTP-bound GTPase Ran binds to importin β and dissociates the import complex. Next, Ran/GTP transports the complex across the NPC into the cytoplasm. Hydrolysis of GTP to GDP is stimulated by Ran binding protein 1 and Ran GTPase activating protein 1 in the cytoplasm. Conformational rearrangements in Ran/GDP lead to the dissociation of importin β to be free for the next cycle. Created with BioRender.com.