Heterogeneous expression of claudin-4 in human colorectal cancer: decreased claudin-4 expression at the invasive front correlates cancer invasion and metastasis.
OBJECTIVE
Claudin-4 plays a key role in constructing the tight junction (TJ), and altered claudin-4 expression has been documented in various human malignancies; however, little is known about the biological significance of claudin-4 in colorectal cancers (CRCs). The aim of this study is to investigate the significance of claudin-4 expression in CRC and its association with clinicopathological factors.


METHODS
The levels of claudin-4 expression in a total of 129 CRCs and 44 metastatic tumors were examined by immunohistochemistry. A small interfering RNA (siRNA)-mediated claudin-4 knockdown examination was also conducted to assess the biological role(s) of claudin-4 in cultured cells.


RESULTS
Expression of claudin-4 at the intercellular membrane was well preserved at the surface of the tumor; however, decreased claudin-4 expression was detected in 57% of CRCs, particularly at the invasive front. Interestingly, decreased claudin-4 expression was detected in metastatic lesions of CRC. The siRNA-mediated claudin-4 knockdown in SW480 claudin-4-positive CRC cells upregulated cell motility, whereas no significant change was detected in cell proliferation.


CONCLUSIONS
These observations suggested that disruption of claudin-4-mediated TJ construction enhances cancer cell invasion and metastasis in human CRC. Claudin-4 might be a good biomarker for diagnosing the risk of distant metastasis.
Ueda
Junya
J
Division of Surgical Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Kobe, Japan.
Semba
Shuho
S
Chiba
Hideki
H
Sawada
Norimasa
N
Seo
Yasushi
Y
Kasuga
Masato
M
Yokozaki
Hiroshi
H
D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D062506:Claudin-4; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering
C568157:CLDN4 protein, human; D062506:Claudin-4; D008565:Membrane Proteins; D034741:RNA, Small Interfering