Abstract
All-trans retinoic acid (RA), which is the dietary bioactive derivative obtained from animal (retinol) and plant sources (beta-carotene), is a physiological lipid signal of both embryonic and postembryonic development. During pregnancy, either RA deficiency or an excessive RA intake is teratogenic. Too low or too high RA affects not only prenatal, but also postnatal, developmental processes such as myelopoiesis and mammary gland morphogenesis. In this review, we mostly focus on emerging RA-regulated epigenetic mechanisms involving RA receptor alpha (RARA) and Annexin A8 (ANXA8), which is a member of the Annexin family, as well as ANXA8 regulatory microRNAs (miRNAs). The first cancer showing ANXA8 upregulation was reported in acute promyelocytic leukemia (APL), which induces the differentiation arrest of promyelocytes due to defective RA signaling caused by RARA fusion genes as the PML-RARA gene. Over the years, ANXA8 has also been found to be upregulated in other cancers, even in the absence of RARA fusion genes. Mechanistic studies on human mammary cells and mammary glands of mice showed that ANXA8 upregulation is caused by genetic mutations affecting RARA functions. Although not all of the underlying mechanisms of ANXA8 upregulation have been elucidated, the interdependence of RA-RARA and ANXA8 seems to play a relevant role in some normal and tumorigenic settings.
Highlights
Egyptians, the Greek scholar Hippocrates, and Chinese Medicine used liver to treat night blindness for thousands of years
A high expression of Annexin A8 (ANXA8) represents a poor prognosis of overall survival and disease-free survival, and significantly correlates with the TNM (T for the size of the tumor and any spread of cancer into nearby tissue, N for the spread of cancer to nearby lymph nodes, and M for metastasis) staging system that was created by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC)
The gene expression profiles of metastatic lymph nodes from oral squamous cell carcinoma (OSCC) patients relative to a control non-cancer cervical lymph node and heterotopic salivary gland tissue identified over eleven thousand genes, and found genes encoding ANXA8, keratin 6C (KRT6C), small proline-rich protein 1B (SPRR1B), and desmoglein 3 (DSG3) that were overexpressed in all metastatic lymph nodes
Summary
Egyptians, the Greek scholar Hippocrates, and Chinese Medicine used liver to treat night blindness for thousands of years. Other scientists confirmed the effects of teratogenic and major birth defects due to an excess of vitamin A in different animal models, as well as the detrimental intake of high levels of vitamin A in the course of pregnancy [3,4,5,16]. Cancer Prevention trial, and the Physicians’ Health Trial, showed that beta-carotene and retinol (vitamin A), rather than preventing cancer, induced detrimental tumorigenic effects in smokers [22,23,24,25]. Overall, these chemoprevention cancer trials revealed that different sources of RA, rather than reducing the incidence of cancer, promoted both cancer growth and invasion [26,27]. The focus of this review is on emerging RA-regulated mechanisms involving specific annexins in APL and other cancers, with a special emphasis on cancers over-expressing ANXA8
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