Upregulated expression of HOXB7 in intrahepatic cholangiocarcinoma is associated with tumor cell metastasis and poor prognosis

Zhenjie Yang,Bin He,Lin Zhou,Yunhao Chen,Jian Wu,Shusen Zheng,Wendi Hu,Haiyang Xie,Longfei Dai,Diyu Chen

doi:10.1038/s41374-018-0150-4

Zhenjie Yang, Bin He + Show 8 more

Open Access

https://doi.org/10.1038/s41374-018-0150-4

Copy DOI

Abstract

Homeobox B7 (HOXB7) protein is reported to be aberrantly expressed in a variety of cancers and to play an important role in multiple cellular processes. However, the specific mechanism by which HOXB7 promotes the malignant progression of intrahepatic cholangiocarcinoma (ICC) remains unclear. Therefore, we used quantitative real-time polymerase chain reaction (PCR) to detect the expression level of HOXB7 in 38 paired ICC tissue samples. Additionally, to assess correlation between HOXB7 and ICC prognosis, we performed immunohistochemistry (IHC) using 122 ICC tissues to detect HOXB7 expression. Cell Counting Kit-8 (CCK-8) and colony formation assays were employed to assess ICC cell proliferation, and Transwell assays were performed to estimate the invasion and migration abilities of ICC cells. The capillary tube formation assay was applied to explore the angiogenic effects of HOXB7. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth and lung metastasis. The results showed higher expression of HOXB7 in ICC tissues than in noncancerous tissues, and this increased expression was significantly associated with a poor prognosis. In addition, HOXB7 overexpression enhanced capillary tube formation, invasion and migration of ICC cells in vitro, whereas HOXB7 knockdown produced the opposite results in vitro. Moreover, the role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that the expression levels of MMP2, MMP9, VEGFa, and IL8 were elevated by HOXB7 and that the ERK pathway was activated. Our results demonstrate the prognostic value of HOXB7 and its role in metastasis and angiogenesis in ICC. HOXB7 upregulated MMP2, MMP9, VEGFa, and IL8 expression via the ERK pathway to accelerate the malignant progression of ICC.

Highlights

Cholangiocarcinoma (CCA) is an epithelial cell malignancy that can originate in different locations of the biliary tree [1] and the second most common primary hepatic neoplasm after hepatocellular carcinoma [2]
To confirm the qRT-polymerase chain reaction (PCR) results, we measured Homeobox B7 (HOXB7) expression in 122 paired intrahepatic cholangiocarcinoma (ICC) and noncancerous tissues by IHC, which revealed that HOXB7 was upregulated in ICC tumors compared with adjacent bile duct tissues (Fig. 1b)
D Pharmacological inhibition of ERK1/2 depressed the effect of HOXB7 on capillary tube formation. e, f Pharmacological inhibition of ERK1/2 depressed the effect of HOXB7 on migration and invasion. *P < 0.05, **P < 0.01, NS no significance been reported to be aberrantly expressed in a variety of cancers, including melanoma [9], breast cancer [10,11,12,13,14,15], gastric cancer [16, 17], liver cancer [18, 19], colorectal cancer [20], and esophageal cancer [21]

Summary

Introduction

Cholangiocarcinoma (CCA) is an epithelial cell malignancy that can originate in different locations of the biliary tree [1] and the second most common primary hepatic neoplasm after hepatocellular carcinoma [2]. The current classification of CCA is based on anatomical location and includes intrahepatic, perihilar, and distal sites. Intrahepatic cholangiocarcinoma (ICC) comprises 8–10% of CCAs and 10–20% of all primary liver tumors. CCA is one of the most fatal cancers, as its 5-year survival rates are only 30–40% after complete resection and its median survival for patients with unresectable disease is only 12–15 months [6].

Methods

Results

Conclusion