Systemic Administration of Small Interfering RNA Targeting Human Nestin Inhibits Pancreatic Cancer Cell Proliferation and Metastasis.
OBJECTIVE
Nestin, a progenitor/stem cell marker, is expressed in human pancreatic cancer, where its expression correlates positively with invasiveness and metastasis. Here, we investigated the inhibition of nestin expression and the regulation of nestin expression.


METHODS
We analyzed the effects of small interfering RNA (siRNA) targeting nestin using pancreatic cancer cell lines.


RESULTS
Nestin siRNA inhibited the growth, migration, invasion, and sphere-forming ability of the pancreatic cancer cell lines. Pancreatic cancer cells cotreated with gemcitabine and nestin siRNA exhibited lower cell viability than cells treated with a control siRNA, gemcitabine alone, or nestin siRNA alone. Cells derived from the metastatic nodules of mice showed higher nestin expression than the parental cells, and nestin expression in pancreatic cancer cells was regulated by methylation of the nestin gene. In an orthotopic implantation model using mice, administration of nestin siRNA significantly decreased primary and metastatic tumor formation by human pancreatic cancer cells compared to tumor formation in control siRNA-treated mice.


CONCLUSIONS
Nestin plays a key role in pancreatic cancer cell metastasis and stemness and that administration of nestin siRNA may offer a novel therapeutic strategy for pancreatic cancer.
From the *Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku; †Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Bunkyo-ku; and ‡Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Yoko
Y
Matsuda
Toshiyuki
T
Ishiwata
Hisashi
H
Yoshimura
Satoshi
S
Yamashita
Toshikazu
T
Ushijima
Tomio
T
Arai
D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D064231:Nestin / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D000067492:RNAi Therapeutics; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C577484:NES protein, human; D064231:Nestin; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D000093542:Gemcitabine