Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer.
MUC5AC, a high molecular weight glycoprotein, is overexpressed in the ductal region of human pancreatic cancer but is not detectable in the normal pancreas, suggesting its association with disease development. In the present study, we investigated the in vitro and in vivo effects of MUC5AC knockdown by short interfering RNA (siRNA) in the MUC5AC-overexpressing SW1990 and BxPC3 human pancreatic cancer cell lines in order to clarify its function. Significant decreases in the expression levels of MUC5AC mRNA and protein were observed in SW1990 and BxPC3 cells that had been stably transfected with a MUC5AC siRNA expression vector (SW1990/si-MUC5AC and BxPC3/si-MUC5AC cells) compared to those in cells transfected with an si-mock vector (SW1990/si-mock and BxPC3/si-mock cells). In in vitro studies, neither type of MUC5AC-knockdown cell showed any difference in cell survival, proliferation, or morphology from the si-mock cells or parental cells. However, in vivo xenograft studies demonstrated that MUC5AC knockdown significantly reduced the tumorigenicity and suppressed the tumor growth of si-MUC5AC cells compared to those of the si-mock cells. Immunohistochemical analysis revealed that CD45R/B220+ and Gr-1+ cells had infiltrated into the tumor tissue of the SW1990/si-MUC5AC cells. Furthermore, cancer-associated antigen specific antibodies were detected at high levels in the sera from the SW1990/si-MUC5AC cell-bearing mice. These results suggest that tumor-associated MUC5AC expressed on the surface of pancreatic cancer cells supports the escape of pancreatic cancer cells from immunosurveillance. The present findings highlight a new dimension of MUC5AC as a functional immunosuppressive agent and its important role in pancreatic cancer progression.
Biomedical Research Laboratories, Kureha Corporation, Hyakunin-cho, Tokyo, Japan.
Hirotaka
H
Hoshi
Tetsuji
T
Sawada
Motoyuki
M
Uchida
Hikaru
H
Saito
Hiroko
H
Iijima
Mikako
M
Toda-Agetsuma
Tsutomu
T
Wada
Sadaaki
S
Yamazoe
Hiroaki
H
Tanaka
Kenjiro
K
Kimura
Anna
A
Kakehashi
Min
M
Wei
Kosei
K
Hirakawa
Hideki
H
Wanibuchi
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055271:Mucin 5AC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D019139:Tumor Escape / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C524678:MUC5AC protein, human; D055271:Mucin 5AC; D034741:RNA, Small Interfering