Roles of flotillins in tumors

Abstract

The identification and use of molecular biomarkers have greatly improved the diagnosis and treatment of malignant tumors. However, a much deeper understanding of oncogenic proteins is needed for the benefit to cancer patients. The lipid raft marker proteins, flotillin-1 and flotillin-2, were first found in goldfish retinal ganglion cells during axon regeneration. They have since been found in a variety of cells, mainly on the inner surface of cell membranes, and not only act as a skeleton to provide a platform for protein-protein interactions, but also are involved in signal transduction, nerve regeneration, endocytosis, and lymphocyte activation. Previous studies have shown that flotillins are closely associated with tumor development, invasion, and metastasis. In this article, we review the functions of flotillins in relevant cell processes, their underlying mechanisms of action in a variety of tumors, and their potential applications to tumor molecular diagnosis and targeted therapy.

Keywords: Flotillins; Tumor; Lipid raft protein; Signal transduction.

Fig. 1

Structures of flotillin-1 (a) and flotillin-2 (b) proteins CRAC: cholesterol recognition/interaction amino acid; SPFH: stomatin/prohibitin/flotillin/HflK; PHB: prohibitin homology

Fig. 2

Mechanisms of flotillin functions in tumors (a) Flotillin-1 inhibits FOXO3a to down-regulate p21^Cip1 and p27^Kip1 and up-regulate CDK1 expression, and subsequently promote tumor progression. It can also up-regulate the expression level of TNF-α receptor and then promote cell proliferation and tumor cell growth. miR-124 and miR-485-5p target flotillin-1 to regulate tumor cell proliferation, migration, and lymph node metastasis. (b) Flotillin-2 activates the PI3K/AKT/mTOR, PI3K/AKT/FOXO, and PI3K/AKT/MAPK pathways to promote cell proliferation, progression of the cell cycle, and cell migration, respectively. It can also activate NF-κB signaling to up-regulate MMP2, MMP7, and MMP9 and then promote cell migration. miR-34a targets flotillin-2 to regulate cell proliferation, migration, and invasion