PLCE1 Promotes Esophageal Cancer Cell Progression by Maintaining the Transcriptional Activity of Snail

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2017-03, Vol.19 (3), p.154-164
• Main Authors: Zhai, Shicong, Liu, Cui, Zhang, Lichen, Zhu, Jian, Guo, Jiqiang, Zhang, Jinghang, Chen, Zhijun, Zhou, Wenping, Chang, Tingmin, Xu, Siguang, Qi, Yijun, Zhuang, Ting, Yu, Na, Wang, Weilong, Wang, Hui, Yu, Sifan, Li, Xiumin
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Cluster Analysis; CRISPR-Cas Systems; Disease Models, Animal; Disease Progression; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Female; Gene Editing; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Gene Silencing; Gene Targeting; Heterografts; Humans; Mice; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Oncology; Phosphoinositide Phospholipase C - genetics; Phosphoinositide Phospholipase C - metabolism; Snail Family Transcription Factors - metabolism; Transcriptional Activation; Tumor Burden
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2016.12.007

Abstract Esophageal cancer is among the most deadly malignant diseases. However, the genetic factors contributing to its occurrence are poorly understood. Multiple studies with large clinic-based cohorts revealed that variations of the phospholipase C epsilon (PLCE1) gene were associated with esophageal cancer susceptibility. However, the causative role of PLCE1 in esophageal cancer is not clear. We inactivated the functional alleles of PLCE1 by CRISPR/Cas9 genome editing technology. The resultant PLCE1 inactivated cells were analyzed both in vitro and in vivo . Our results showed that loss of PLCE1 dramatically decreased the invasion and proliferation capacity of esophageal carcinoma cells in vitro . Moreover, such PLCE1 inactivated tumor grafts exhibited significantly decreased tumor size in mice. We found that PLCE1 was required to maintain protein level of snail a key transcription factor responsible for invasion. Our further transcriptomic data revealed that deficient cells were significantly decreased in expression of genes enriched as targets of Snail. Strikingly, recovery of Snail protein at least partially rescued the invasion and proliferation capacity in PLCE1 inactivated cells. In ESCC clinical specimens, PLCE1 was correlated with tumor stage ( P < .0001). Interestingly, PLCE1 expression was positively correlated Snail by immunohistochemistry in such specimens ( P < .0001). Therefore, our functional experiments showed the essential roles of PLCE1 in esophageal carcinoma cells and provided evidences that targeting PLCE1 and its downstream molecules could be effective therapies for esophageal cancer.