Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin.
OBJECTIVE
Lgr5 is a member of the G protein receptor super-family and was shown recently to be a stem cell marker for cells with intestinal differentiation. Its over-expression has been demonstrated in hepatocellular, basal cell carcinoma, and ovarian cancers but the underlying mechanisms are poorly understood. The aim of this study was to investigate if Lgr5 over-expression was correlated with human colorectal carcinogenesis and its potential correlation with beta-catenin.


METHODS
The study was carried out on a tissue microarray that consisted of 102 colorectal carcinomas (CRC; M:F = 55:47), 18 colon adenoma, and 12 colon normal mucosa cases. Immunostains were performed with the standard EnVision method with primary antibodies against Lgr5, beta-catenin, and p53 antigens. Immunoreactivity of neoplastic cells to each antibody was double-blindly semi-quantified by two pathologists and the data were analyzed with the Chi-square and Spearman rank correlation tests. Subsequently, expression of Lgr5 in tissue sections of tumor centre and invasive margins of 21 cases of CRC certified to be immunoreactive of Lgr5 in TMA were evaluated and possible differences of Lgr5 expression between them were analyzed.


RESULTS
Lgr5 immunoreactivity was observed only in single cells in the base of normal colon mucosal crypts but high in 28% (five out of 18) adenomas, and significantly higher in 54% (55/102, p = 0.016) CRC cases. In normal mucosa, adenoma, and CRC, beta-catenin expression was seen in 25% (three out of 12), 27% (five out of 18), and 81% (83/102) cases, respectively, in contrast to 0, 0, and 40% (41/102) for p53 expression, respectively. In CRC, Lgr5 expression was more intense in women than men (p < 0.0001), and positively correlated with beta-catenin expression (p < 0.001), but not with patients' ages, tumor sizes, nodal status, TNM stages, and p53 expression. Different expression of Lgr5 between tumor centre and invasive margins was not found (p > 0.05).


CONCLUSIONS
The results suggest that up-regulation of Lgr5 expression, especially in female patients, may play an important role in colorectal carcinogenesis, probably through the WNT/beta-catenin pathway, but not involve the progression of the CRC.
Fan
Xiang-Shan
XS
Department of Pathology, Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, People's Republic of China.
Wu
Hong-Yan
HY
Yu
Hui-Ping
HP
Zhou
Qiang
Q
Zhang
Yi-Fen
YF
Huang
Qin
Q
D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin