Skoudy Anouchka, Hernández-Muñoz Inmaculada, Navarro Pilar
Cancer Research Programme, IMIM (Institut de Recerca Hospital del Mar), Dr Aiguader 88, Barcelona, Spain.
J Gastrointest Cancer. 2011 Jun;42(2):76-84. doi: 10.1007/s12029-011-9258-0.
Deregulated expression/activation of transcription factors is a key event in the establishment and progression of human cancer. Furthermore, most oncogenic signaling pathways converge on sets of transcription factors that ultimately control gene expression patterns resulting in cancer development, progression, and metastasis.
Ductal pancreatic adenocarcinoma (PDA) is the main type of pancreatic cancer and the fourth leading cause of cancer mortality in the Western world. The early stage of the disease is characterized by pancreatic intraepithelial neoplasia lesions bearing mutations in the K-RAS proto-oncogene, which progress to malignant PDA by accumulating additional mutations in the tumor suppressor gene CDKN2A (p16) and in SMAD4 and TP53 transcription factors. The involvement of other signaling pathways in PDA development and progression is an active area of research which may help to clarify the critical steps of this devastating disease.
In this regard, several in vitro and in vivo data have demonstrated the contribution of the transcription factor c-Myc to pancreatic carcinogenesis although the molecular mechanisms are poorly understood. c-Myc is a proto-oncogene which has a pivotal function in growth control, differentiation and apoptosis and is known to act as a downstream transcriptional effector of many signaling pathways involved in these processes. It is regulated at multiple levels and its abnormal expression contributes to the genesis of many human tumors.
This review focuses on the role of c-Myc in pancreatic embryonic development and homeostasis as well as its involvement on pancreatic tumorigenesis. Evidences showing that c-Myc function is highly dose and cell context dependent, together with its recently demonstrated ability to reprogram somatic cells towards a pluripotent stem cell-like state, indicate that the role of c-Myc in pancreas pathophysiology might have been previously underscored.
转录因子的表达失调/激活是人类癌症发生和发展的关键事件。此外，大多数致癌信号通路都汇聚于一些转录因子，这些转录因子最终控制基因表达模式，导致癌症的发生、发展和转移。
导管腺癌（PDA）是胰腺癌的主要类型，也是西方世界癌症死亡的第四大主要原因。该疾病的早期阶段以胰腺上皮内瘤变病变为特征，这些病变在K-RAS原癌基因中发生突变，通过在肿瘤抑制基因CDKN2A（p16）以及SMAD4和TP53转录因子中积累额外突变，进展为恶性PDA。其他信号通路在PDA发生和发展中的作用是一个活跃的研究领域，这可能有助于阐明这种毁灭性疾病的关键步骤。
在这方面，一些体外和体内数据已经证明转录因子c-Myc对胰腺癌发生的作用，尽管其分子机制尚不清楚。c-Myc是一种原癌基因，在生长控制、分化和凋亡中具有关键作用，并且已知它是参与这些过程的许多信号通路的下游转录效应器。它在多个水平受到调控，其异常表达导致许多人类肿瘤的发生。
本综述重点关注c-Myc在胰腺胚胎发育和稳态中的作用以及它在胰腺肿瘤发生中的参与情况。表明c-Myc功能高度依赖剂量和细胞背景的证据，以及其最近证明的将体细胞重编程为多能干细胞样状态的能力，表明c-Myc在胰腺病理生理学中的作用可能此前未得到充分重视。
