CCN1诱导食管癌细胞凋亡的分子生物学途径

食管癌是引起我国死亡人数最多的四大癌症之一，其中以鳞癌居多，但近年来患腺癌的人数也迅速上升。其主要根源是胃食管反流。现多以抑酸药物治疗,但收效欠佳且多副作用,为此，美国FDA已发多次警告。好的抗癌药物不仅要能杀死癌细胞，还不可伤及正常组织。TRAIL 就是这样,因其受体仅见于癌细胞的表面，所以，对正常组织无害。然而，有些癌细胞对TRAIL不敏感，需先致敏，方能见效。食管癌便是如此。因此，寻找TRAIL致敏剂成为当前癌症研究的首要任务。根据我们的研究，CCN1具备TRAIL致敏剂的许多特征。它能改变TRAIL及其受体在癌细胞中的表达，从而促成癌细胞凋亡。本研究旨在探讨这一过程的分子生物学机理。我们将采用体外和体内相结合的实验手段，确定CCN1在癌细胞表面的受体，及其改变TRAIL表达的信号传导途径。为寻找更理想的抗癌药物奠定生物学基础，同时也为深入剖析TRAIL的致敏原理铺砖引路。

Esophageal cancer is one of the four deadliest cancers in China。While most are squamous carcinoma, adenocarcinoma has been rising dramatically in recent years. This rise is largely associated with the fast growth of obese population. Extra body weight puts constant pressure on the stomach, forces the gastric acid along with the bile salts from the duodenum to go up into the esophagus and causes chronic inflammation. In order to protect the epithelial lining from the frequent episodes of acid/bile attacks, the squamous epithelium of the esophagus transforms into intestinal columnar phenotype, a precursor for adenocarcinoma. Current treatment strategy mainly relies on acid suppressive medications. However, more and more studies have reported various side-effects associated with this type of drugs, including elevated risk of malignancy. A good anti-cancer drug is supposed to not only kill the transformed cells, but also harmless to the normal tissue. TRAIL is such an example. TRAIL can induce apoptosis in a variety of cancer cells that are resistant to other chemotherapy without causing any side-effect, because its death receptors are almost exclusively found on the cancer cells. However, increasing evidence indicates that some cancer cells are not sensitive to TRAIL treatment, despite the expression of the death receptors, and require a second agent to pre-sensitize them. Therefore, searching for the right TRAIL sensitizer becomes a top priority in modern cancer research. Based on our study, CCN1 has many characteristics of such an agent. CCN1 is matricellular protein that can alter the expressions of TRAIL and its receptors in esophageal tumor cells, and make them vulnerable to TRAIL apoptotic activity. The aim of this study is to elucidate the molecular mechanisms of this action, and to establish the biological basis for possible use of CCN1 in future cancer treatment. In particular, we will use in vitro and in vivo experimental strategies to find out what receptor mediates CCN1 actions in esophageal cancer and what signaling pathways sensitize TRAIL and lead to cell death.