Cytoplasmic Kaiso is associated with poor prognosis in non-small cell lung cancer.
BACKGROUND
Kaiso has been identified as a new member of the POZ-zinc finger family of transcription factors that are implicated in development and cancer. Although controversy still exists, Kaiso is supposed to be involved in human cancer. However, there is limited information regarding the clinical significance of cytoplasmic/nuclear Kaiso in human lung cancer.


METHODS
In this study, immunohistochemical studies were performed on 20 cases of normal lung tissues and 294 cases of non-small cell lung cancer (NSCLC), including 50 cases of paired lymph node metastases and 88 cases with complete follow-up records. Three lung cancer cell lines showing primarily nuclear localization of Kaiso were selected to examine whether roles of Kaiso in cytoplasm and in nucleus are identical. Nuclear Kaiso was down-regulated by shRNA technology or addition a specific Kaiso antibody in these cell lines. The proliferative and invasive abilities were evaluated by MTT and Matrigel invasive assay, transcription of Kaiso's target gene matrilysin was detected by RT-PCR.


RESULTS
Kaiso was primarily expressed in the cytoplasm of lung cancer tissues. Overall positive cytoplasmic expression rate was 63.61% (187/294). The positive cytoplasmic expression of Kaiso was higher in advanced TNM stages (III+IV) of NSCLC, compared to lower stages (I+II) (p = 0.019). A correlation between cytoplasmic Kaiso expression and lymph node metastasis was found (p = 0.003). In 50 paired cases, cytoplasmic expression of Kaiso was 78.0% (41/50) in primary sites and 90.0% (45/50) in lymph node metastases (p = 0.001). The lung cancer-related 5-year survival rate was significantly lower in patients who were cytoplasmic Kaiso-positive (22.22%), compared to those with cytoplasmic Kaiso-negative tumors (64.00%) (p = 0.005). Nuclear Kaiso staining was seen in occasional cases with only a 5.10% (15/294) positive rate and was not associated with any clinicopathological features of NSCLC. Furthermore, after the down-regulation of the nuclear expresses Kaiso in vitro, both proliferative and invasive abilities of three cancer cell lines were significantly enhanced, along with the up-regulation of Kaiso target gene, matrilysin.


CONCLUSIONS
Our data suggest cytoplasmic Kaiso expression is associated with poor prognosis of NSCLC and various subcellular localizations of Kaiso may play differential biological roles in NSCLC.
Dai
Shun-Dong
SD
Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, PR China. dddsddd111@yahoo.com.cn
Wang
Yan
Y
Miao
Yuan
Y
Zhao
Yue
Y
Zhang
Yong
Y
Jiang
Gui-Yang
GY
Zhang
Peng-Xin
PX
Yang
Zhi-Qiang
ZQ
Wang
En-Hua
EH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
D034741:RNA, Small Interfering; D014157:Transcription Factors; C492254:ZBTB33 protein, human; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7