Glucose-regulated protein 78 regulates multiple malignant phenotypes in head and neck cancer and may serve as a molecular target of therapeutic intervention.
Glucose-regulated protein 78 (Grp78) is an endoplasmic reticulum chaperone protein and is overexpressed in various cancers. However, it is unclear how significance of this molecule play an active role contributing to the oncogenic effect of head and neck cancer (HNC). To investigate the potential function of Grp78, six HNC cell lines were used. We found that Grp78 is highly expressed in all six cell lines and many of the proteins were localized in the periphery regions, implying other function of this molecule aside from endoplasmic reticulum stress response. Knockdown of Grp78 by small interfering RNA significantly reduced cell growth and colony formation to 53% to 12% compared with that of controls in all six HNC cell lines. Using in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also inhibited to 23% to 2% in all these cell lines tested. In vivo xenograft studies showed that administration of Grp78-small interfering RNA plasmid into HNC xenografts significantly inhibited both tumor growth in situ (>60% inhibition at day 34) and liver metastasis (>90% inhibition at day 20). Our study showed that Grp78 actively regulates multiple malignant phenotypes, including cell growth, migration, and invasion. Because knockdown Grp78 expression succeeds in the reduction of tumor growth and metastatic potential, this molecule may serve as a molecular target of therapeutic intervention for HNC.
Chiu
Ching-Chi
CC
Graduate Institute of Biomedical Science, Chang Gung University, Taoyuan, Taiwan.
Lin
Chien-Yu
CY
Lee
Li-Yu
LY
Chen
Yin-Ju
YJ
Kuo
Ting-Fang
TF
Chang
Joseph Tung-Chieh
JT
Liao
Chun-Ta
CT
Wang
Hung-Ming
HM
Yen
Tzu-Chen
TC
Shen
Chia-Rui
CR
Liao
Shuen-Kuei
SK
Cheng
Ann-Joy
AJ
D000328:Adult; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000091342:Endoplasmic Reticulum Chaperone BiP; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D034741:RNA, Small Interfering