CXCL12 expression in intrahepatic cholangiocarcinoma is associated with metastasis and poor prognosis

• Published in: Cancer science Vol. 110; no. 10; pp. 3197 - 3203
• Main Authors: Miyata, Tatsunori, Yamashita, Yo‐Ichi, Yoshizumi, Tomoharu, Shiraishi, Masayuki, Ohta, Masayuki, Eguchi, Susumu, Aishima, Shinichi, Fujioka, Hikaru, Baba, Hideo
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2019; John Wiley and Sons Inc
• Subjects: Aged; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; cDNA microarray; Cell adhesion & migration; Cell Line, Tumor; Cell lines; Cell Movement; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; CXCL12; CXCL12 protein; DNA microarrays; Experiments; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hepatectomy; Humans; Immunohistochemistry; intrahepatic cholangiocarcinoma; Liver; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - secondary; Medical prognosis; Metastases; Metastasis; Middle Aged; Oligonucleotide Array Sequence Analysis - methods; Original; Paraffin; Patients; Prognosis; Studies; Surgery; Therapeutic applications; Up-Regulation; cDNA microarray; CXCL12; metastasis; prognosis; intrahepatic cholangiocarcinoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14151

Intrahepatic cholangiocarcinoma is a rare malignant biliary neoplasm that causes a poor prognosis even after curative hepatectomy. Liver metastasis is the major recurrence pattern of intrahepatic cholangiocarcinoma; therefore, the prevention of liver metastasis is a desirable objective. The aim of this study is to identify gene(s) related to liver metastasis of intrahepatic cholangiocarcinoma and to examine the inhibitory effects on metastasis of intrahepatic cholangiocarcinoma by controlling such gene(s). We collected 3 pairs of intrahepatic cholangiocarcinoma frozen samples, and 36 pairs (primary and metastatic lesions) of intrahepatic cholangiocarcinoma formalin‐fixed paraffin‐embedded samples, from patients who underwent surgical resection at hospitals related to the Kyushu Study Group of Liver Surgery between 2002 and 2016. We carried out cDNA microarray analyses and immunohistochemistry to identify candidate genes, and evaluated one of them as a therapeutic target using human cholangiocarcinoma cell lines. We identified 4 genes related to liver metastasis using cDNA microarray, and found that CXCL12 was the only gene whose expression was significantly higher in liver metastasis than in primary intrahepatic cholangiocarcinoma by immunohistochemistry (P = .003). In prognosis, patients in the high CXCL12 group showed a significantly poor prognosis in disease‐free (P < .0001) and overall survival (P = .0004). By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines. Therefore, CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma. CXCL12 was significantly more highly expressed in liver metastasis than in primary intrahepatic cholangiocarcinoma. In terms of prognosis, patients in the high CXCL12 group showed a significantly poorer prognosis in disease‐free and overall survival than those in the low CXCL12 group. CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.