PLCE1 Promotes Esophageal Cancer Cell Progression by Maintaining the Transcriptional Activity of Snail.
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.
Center for Cancer Research, Xinxiang Medical University, Xinxiang, Henan, China; Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Shicong
S
Zhai
School of Nursing, Xinxiang Medical University, Henan, China.
Cui
C
Liu
School of Laboratory Medicine, Xinxiang Medical University.
Lichen
L
Zhang
School of Laboratory Medicine, Xinxiang Medical University; Research Center for Immunology, Xinxiang Medical University, Henan, China.
Jian
J
Zhu
Research Center for Immunology, Xinxiang Medical University, Henan, China.
Jiqiang
J
Guo
Department of Pathology, the First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
Jinghang
J
Zhang
Department of Thoracic Surgery, the First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
Zhijun
Z
Chen
Lymphoma Institute, Zhengzhou, Henan Cancer Hospital, Zhengzhou, Henan, China.
Wenping
W
Zhou
Department of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
Tingmin
T
Chang
Institute of Lung and Molecular Therapy, Xinxiang Medical University, China.
Siguang
S
Xu
Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, China.
Yijun
Y
Qi
School of Laboratory Medicine, Xinxiang Medical University; Research Center for Immunology, Xinxiang Medical University, Henan, China.
Ting
T
Zhuang
Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Na
N
Yu
Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Weilong
W
Wang
Ontario Cancer Institute, Campbell Family Institute for Breast Cancer Research, University of Toronto, Toronto, Canada.
Hui
H
Wang
Research Center for Immunology, Xinxiang Medical University, Henan, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Renal cancer and Melanoma, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
Sifan
S
Yu
Center for Cancer Research, Xinxiang Medical University, Xinxiang, Henan, China; Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. Electronic address: lxm3029981@126.com.
Xiumin
X
Li
D000818:Animals; D001483:Base Sequence; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D016000:Cluster Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000072669:Gene Editing; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D018390:Gene Targeting; D064593:Heterografts; D006801:Humans; D051379:Mice; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D054801:Phosphoinositide Phospholipase C / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D047368:Tumor Burden
D000071250:Snail Family Transcription Factors; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon