Mongan Nigel P, Gudas Lorraine J
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
Differentiation. 2007 Nov;75(9):853-70. doi: 10.1111/j.1432-0436.2007.00206.x. Epub 2007 Jul 18.
Retinoids (retinol [vitamin A] and its biologically active metabolites) are essential signaling molecules that control various developmental pathways and influence the proliferation and differentiation of a variety of cell types. The physiological actions of retinoids are mediated primarily by the retinoic acid receptors alpha, beta, and gamma (RARs) and rexinoid receptors alpha, beta, and gamma. Although mutations in RARalpha, via the PML-RARalpha fusion proteins, result in acute promyelocytic leukemia, RARs have generally not been reported to be mutated or part of fusion proteins in carcinomas. However, the retinoid signaling pathway is often compromised in carcinomas. Altered retinol metabolism, including low levels of lecithin:retinol acyl trasferase and retinaldehyde dehydrogenase 2, and higher levels of CYP26A1, has been observed in various tumors. RARbeta(2) expression is also reduced or is absent in many types of cancer. A greater understanding of the molecular mechanisms by which retinoids induce cell differentiation, and in particular stem cell differentiation, is required in order to solve the issue of retinoid resistance in tumors, and thereby to utilize RA and synthetic retinoids more effectively in combination therapies for human cancer.
维甲酸（视黄醇[维生素A]及其生物活性代谢产物）是重要的信号分子，可控制各种发育途径，并影响多种细胞类型的增殖和分化。维甲酸的生理作用主要由维甲酸受体α、β和γ（RARs）以及类视黄醇X受体α、β和γ介导。虽然RARα通过PML-RARα融合蛋白发生突变会导致急性早幼粒细胞白血病，但在癌症中，一般尚未报道RARs发生突变或成为融合蛋白的一部分。然而，维甲酸信号通路在癌症中常常受到损害。在各种肿瘤中已观察到视黄醇代谢改变，包括卵磷脂：视黄醇酰基转移酶和视黄醛脱氢酶2水平降低，以及CYP26A1水平升高。在许多类型的癌症中，RARβ(2)的表达也会降低或缺失。为了解决肿瘤中维甲酸耐药性问题，从而更有效地将视黄酸（RA）和合成维甲酸用于人类癌症的联合治疗，需要更深入地了解维甲酸诱导细胞分化，特别是干细胞分化的分子机制。
