Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines.
Pancreatic adenocarcinoma is one of the most deadly malignancies, and endometrial cancer represents the most common gynecologic cancer in the USA. Better understanding on the pathologic mechanisms and pathways is required for effective treatment of these malignancies. Recently, human epididymis protein 4 (HE4 or WFDC2), a secretory glycoprotein, was found to be overexpressed in pancreatic and endometrial cancers. In addition, studies have shown that HE4 overexpression in endometrial cancer cell lines led to faster cancer progression in a mouse subcutaneous model. These findings raise a question on the role(s) of secretory, extracellular HE4 in cancer development. In the present study, we found that treatment of pancreatic and endometrial cancer cell lines with purified, extracellular HE4 protein led to a significant increase in cell viability and proliferation. Moreover, extracellular HE4 protein was able to increase DNA synthesis, and modulate the mRNA and protein levels of cell cycle marker PCNA and cell cycle inhibitor p21. These effects appeared to be robust and sustainable and required a relatively low concentration of HE4 protein. The findings indicated the secreted, extracellular HE4 may carry some physiopathological functions. Via paracrine/endocrine actions, circulatory HE4 produced by malignant cells may contribute to pancreatic and endometrial cancer progression and/or metastasis.
Department of Histology and Embryology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China.
Qinsheng
Q
Lu
Department of Histology and Embryology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China.
Haibin
H
Chen
Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery, Memorial Health University Medical Center, Savannah, GA 31404, USA.
Christopher
C
Senkowski
School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu 213164, P.R. China.
Jianhao
J
Wang
Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA.
Xue
X
Wang
Department of Surgery and Surgical Oncology, Beth Israel Medical Center, New York, NY 10003, USA.
Steven
S
Brower
Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA.
Wayne
W
Glasgow
Department of Obstetrics and Gynecology, Memorial Health University Medical Center, Savannah, GA 31404, USA.
David
D
Byck
Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA.
Shi-Wen
SW
Jiang
Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA.
Jinping
J
Li
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D000081102:WAP Four-Disulfide Core Domain Protein 2
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D011994:Recombinant Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human