Overexpression of PIN1 Enhances Cancer Growth and Aggressiveness with Cyclin D1 Induction in EBV-Associated Nasopharyngeal Carcinoma.
BACKGROUND
Nasopharyngeal carcinoma (NPC) is a peculiar Epstein Barr virus (EBV)-associated malignancy that is prevalent in South-East Asia. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) isomerizes specific phosphorylated amino acid residues, which makes it an important regulator in cell survival and apoptosis. In this study, we investigated the contribution made by PIN1 in NPC tumorigenesis and PIN1's potential role as a therapeutic target.


METHODS
The expression of PIN1 was examined in a panel of NPC cell lines, xenografts and primary tumors. The functional roles of PIN1 in NPC cells were elucidated by the knockdown and overexpression of PIN1 in in vitro and in vivo nude mice models by siRNA and lenti-viral transfection, respectively. The antitumor effects of the PIN1 inhibitor Juglone in NPC cells were also evaluated.


RESULTS
We revealed the consistent overexpression of PIN1 in almost all EBV-associated NPC cell lines, xenografts and primary tumors. PIN1 suppression was capable of inhibiting cyclin D1 expression and activating caspase-3 in NPC cells. It positively regulated NPC cell proliferation, colony formation and anchorage-independent growth. The inhibition of PIN1 suppressed tumor growth in vitro and in vivo.


CONCLUSIONS
This study demonstrates the oncogenic role of PIN1 in NPC tumorigenesis, and shows that its overexpression can enhance tumor cell growth via the upregulation of cyclinD1. Our findings inform the development of novel treatments targeting PIN1 for NPC patients.
Department of Oral Pathology, Guangdong Provincial Key Laboratory of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China.|Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Meng
M
Xu
Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Chartia Ching-Mei
CC
Cheung
Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Chit
C
Chow
Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Samantha Wei-Man
SW
Lun
Department of Surgery, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Siu-Tim
ST
Cheung
Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Kwok-Wai
KW
Lo
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D019938:Cyclin D1; D053148:Caspase 3; C005134:juglone