Oncotarget

Research Papers:

Interaction of KLF6 and Sp1 regulates basigin-2 expression mediated proliferation, invasion and metastasis in hepatocellular carcinoma

Ling-Min Kong _, Li Yao, Ning Lu, Ya-Lu Dong, Jing Zhang, Yong-Qiang Wang, Lili Liu, He-Long Zhang, Jian-Guo Huang and Cheng-Gong Liao

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Oncotarget. 2016; 7:27975-27987. https://doi.org/10.18632/oncotarget.8564

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Abstract

Ling-Min Kong1,*, Li Yao2,*, Ning Lu3,*, Ya-Lu Dong3, Jing Zhang3, Yong-Qiang Wang3, Lili Liu4,5, He-Long Zhang4,5, Jian-Guo Huang3, Cheng-Gong Liao3,4,5

1Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi’an, 710032, P. R. China

2Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, P. R. China

3Department of Oncology, Urumqi General Hospital of Lanzhou Military Command of PLA, Urumqi, 830000, P. R. China

4Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, P. R. China

5Cancer Institute, Fourth Military Medical University, Xi’an, 710038, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Cheng-Gong Liao, email: [email protected]

Jian-Guo Huang, email: [email protected]

He-Long Zhang, email: [email protected]

Keywords: KLF6, Sp1, basigin-2, hepatocellular carcinoma, metastasis

Received: August 10, 2015    Accepted: March 26, 2016    Published: April 4, 2016

ABSTRACT

Accumulating evidence suggests that the tumor suppressor gene Krüppel-like factor 6 (KLF6) plays important roles in both development and progression of cancer. However, the role of KLF6 in hepatocellular carcinoma (HCC) remains unclear. Cancer-related molecule basigin-2 plays an important role in HCC progression and metastasis. Sp1, one of Sp/KLFs family members, regulates basigin-2 expression in HCC. The involvement of KLFs in basigin-2 regulation and HCC progression and metastasis has not been investigated. We first measured KLF6 expression levels in 50 pairs of HCC and adjacent normal tissues (ANTs) by immunohistochemistry. Specifically, low KLF6 expression but high Sp1 and basigin-2 expression were found in HCC tissues. By contrast, the ANTs showed high KLF6 expression but low Sp1 and basigin-2 expression. Kaplan–Meier analysis showed that higher expression of KLF6 was associated with better overall survival. The survival rate of KLF6-negative patients was lower than that of KLF6-positive patients (P = 0.015). We also found that KLF6 binds to the basigin-2 and Sp1 promoters and decreases their expression. Thus, we identified a microcircuitry mechanism in which KLF6 can repress basigin-2 expression directly by binding to its promoter or indirectly by inhibiting the expression of the transcription factor Sp1 to block gene expression. Additionally, overexpression of KLF6 suppressed the invasion, metastasis and proliferation of HCC cells in vitro and in vivo by targeting basigin-2. Our study provides new evidence that interaction of KLF6 and Sp1 regulates basigin-2 expression in HCC and that KLF6 represses the invasive and metastatic capacities of HCC through basigin-2.


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