title: p21-Activated Kinases 1, 2 and 4 in Endometrial Cancers: Effects on Clinical Outcomes and Cell Proliferation.
abstract: p21-activated kinases (Paks) are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028) and cytoplasmic p-Pak2 (P = 0.048) expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05). Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001). On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05) while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05). Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026). Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα) and progestogen receptor (PR) expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 are involved in the pathogenesis of endometrial cancer especially in postmenopausal women. Pak1 promote endometrial cancer cell proliferation, particular in type I endometrioid carcinoma. Cytoplasmic Pak4 can be potential prognostic marker in endometrial cancer.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China; Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Michelle K Y
authors.initials: MK
authors.lastname: Siu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Daniel S H
authors.initials: DS
authors.lastname: Kong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Sheila Y P
authors.initials: SY
authors.lastname: Ngai
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Hoi Yan
authors.initials: HY
authors.lastname: Chan
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Esther S Y
authors.initials: ES
authors.lastname: Wong
authors.affiliation: Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Karen K L
authors.initials: KK
authors.lastname: Chan
authors.affiliation: Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Hextan Y S
authors.initials: HY
authors.lastname: Ngan
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Annie N Y
authors.initials: AN
authors.lastname: Cheung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010766:Phosphorylation; D055815:Young Adult; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C116367:PAK4 protein, human; C515903:PAK1 protein, human; C515907:PAK2 protein, human; D054462:p21-Activated Kinases