Pathobiological functions and clinical implications of annexin dysregulation in human cancers

Abstract

Annexins are an extensive superfamily of structurally related calcium- and phospholipid-binding proteins, largely conserved and widely distributed among species. Twelve human annexins have been identified, referred to as Annexin A1-13 (A12 remains as of yet unassigned), whose genes are spread throughout the genome on eight different chromosomes. According to their distinct tissue distribution and subcellular localization, annexins have been functionally implicated in a variety of biological processes relevant to both physiological and pathological conditions. Dysregulation of annexin expression patterns and functions has been revealed as a common feature in multiple cancers, thereby emerging as potential biomarkers and molecular targets for clinical application. Nevertheless, translation of this knowledge to the clinic requires in-depth functional and mechanistic characterization of dysregulated annexins for each individual cancer type, since each protein exhibits varying expression levels and phenotypic specificity depending on the tumor types. This review specifically and thoroughly examines the current knowledge on annexin dysfunctions in carcinogenesis. Hence, available data on expression levels, mechanism of action and pathophysiological effects of Annexin A1-13 among different cancers will be dissected, also further discussing future perspectives for potential applications as biomarkers for early diagnosis, prognosis and molecular-targeted therapies. Special attention is devoted to head and neck cancers (HNC), a complex and heterogeneous group of aggressive malignancies, often lately diagnosed, with high mortality, and scarce therapeutic options.

Keywords: annexin; biomarker; diagnosis; head and neck cancer; therapeutic target.

FIGURE 1

Schematic overview of annexin structural organization. Purple line, N-terminal tails; Dark blue, C-terminal core domains including four annexin repeats (duplicated to eight in ANXA6); Light blue, annexin repeats harboring non-functional type II calcium binding sites; Key residues are indicated and represented as spheres, and myristoylation as yellow zig-zag lines.

FIGURE 2

Violin plot comparison of annexin expression levels in HNSCC patient samples versus normal adjacent tissue. (A) Transcriptomic expression data were obtained at Xena repository (Goldman et al., 2020) from the TCGA-HNSCC cohort consisting of 44 normal adjacent tissue (N) and 522 primary tumors (T). Transcript per million (TPMs) are shown as log2 transformed (***p < 0.001 by t-test using Welch’s correction; ns, not significant). (B) Proteomic expression data from 72 normal adjacent tissue (N) and 110 primary tumors (T) were obtained from Proteomic Data Commons (https://pdc.cancer.gov/pdc/study/PDC000221). Ion intensity is shown as log2 transformed (***p < 0.001, *p < 0.05 by t-test using Welch’s correction; ns, not significant).

FIGURE 3

Impact of annexin dysregulation on the hallmarks of head and neck cancer. Schematic representation that summarizes current knowledge on annexin dysregulation in relation to the hallmarks of cancer defined by Hanahan and Weinberg. Image created with BioRender.com.