胃肠道息肉恶变是导致黑斑息肉综合征（PJS）患者死亡的主要原因，STK11基因缺陷引起息肉发生，但在恶变中的作用和机制尚不清楚。我们建立了PJS家系标本库，率先发现7个新的STK11基因第XI功能区突变与PJS息肉发生上皮内瘤变有关，且用Protein pathway array（PPA）技术发现p-p38蛋白在XI功能区突变息肉中异常高表达。提示STK11基因第XI功能区突变可能通过激活p38而引起息肉恶变。本项目拟对新入库的38个PJS家系用DNA测序、MLPA等方法结合临床资料，进一步研究STK11基因XI功能区突变与息肉恶变及p-p38的相关性；进而通过质粒转染等技术在体外、体内探讨XI功能区突变通过激活p38对细胞增殖、凋亡、侵袭及裸鼠成瘤的影响。为了解STK11基因第XI功能区突变引起PJS息肉恶变的预警价值、作用机制以及寻找临床治疗靶标和筛选患者实施个体化治疗提供理论依据。

Malignant transformation of gastrointestinal polyps is the major cause of death in Peutz-Jeghers Syndrome (PJS) patients. The STK11 gene deficiency could cause PJS polyps, however, the reason and mechanism for malignant transformation of polyps are not clear yet. In our previous study, we have established a biological specimen bank of Chinese PJS pedigrees according to the standardized procedures and directly interrogated STK11 gene mutations in these patients. We first identified 7 novel mutations in STK11-XI domain were associated with PJS dysplastic polyps. Then, Protein Pathway Array analysis was used to identify PJS polyps protein expression profiles, we found p-p38MAPK protein expression significantly increased in XI domain mutation-polyps compared to I-X domain mutation-polyps. Therefore, we hypothesized the STK11-XI domain mutations could cooperates with p38 activation for malignant transformation of gastrointestinal polyps in Peutz-Jeghers syndrome. In this project, we will further study on the correlation between STK11-XI domain mutations and malignant transformation of PJS polyps in 38 new PJS families, combining Sanger sequence, MLPA and clinical data. In order to explore the role of STK11-XI domain mutations and p38 activation in malignant transformation, we will observe cell proliferation, apoptosis, invasion and tumor formation in vitro and vivo. This study would confirm increased monitoring and surveillance may be recommended for those individuals with these STK11 mutations, provide a novel testable hypothesis for shedding light on our understanding of the development of cancer in this syndrome.