Tumor Biology

, Volume 37, Issue 3, pp 3461–3468 | Cite as

CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma

  • Zeyu Lin
  • Wenbin Li
  • Heyun Zhang
  • Wei Wu
  • Yaorong Peng
  • Yunjie Zeng
  • Yunle Wan
  • Jie Wang
  • Nengtai Ouyang
Original Article


Chemokine ligand 18 (CCL18) has been associated with hepatocellular carcinoma (HCC) metastasis. Here, we demonstrated a novel mechanism through which CCL18 enhances cell migration, invasion, and epithelial–mesenchymal transition (EMT) in HCC. (1) Using immunohistochemistry, we analyzed the expression of PITPNM3, a molecule that correlated with CCL18 signaling, in 149 HCC tissue specimens. The results showed that PITPNM3 expression is highly associated with tumor metastasis and differentiation; (2) in vitro experiments showed that CCL18 enhances cell migration, invasion, and EMT in PITPNM3(+) HCC cells but not in PITPNM3(-) cells. Silencing of PITPNM3 by short interfering RNA (siRNA) inhibited the induction of cell migration, invasion, and EMT by CCL18; (3) Cell migration, invasion, and EMT induced by CCL18 accompanied with the phosphorylation of IKK and IKBα as well as p65 nuclear translocation in PITPNM3(+) HCC cells, but not in the cells that PITPNM3 is silenced with siRNA, implying that the activation of NF-κB signaling is involved in the action of CCL18/PITPNM3. These results suggest that CCL18 enhances HCC cell migration, invasion, and EMT through the expression of PITPNM3 and the activation of the NF-κB signaling pathway.


HCC PITPNM3 Metastasis CCL18 NF-κB EMT 



Hepatocellular carcinoma


Chemokine ligand 18


Epithelial mesenchymal transition


Tumor-associated macrophages




Nuclear factor kappa B


Inhibitor of NF-κB


IκB kinase



This work was supported by grants from Guangdong Provincial Department of Science and Technology (2009B080701088), Guangzhou Bureau of Science and Information Technology (2013 J4100059), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen University, and Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology.

Compliance with ethical standards

The study was performed in accordance with the policies of the Institutional Research Ethics Committee of Sun Yat-Sen Memorial Hospital.

Informed consent

Informed consents were obtained from the patients by BioBank, and the patient’s personally identifiable information such as names, addresses, and contact information were removed.


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Zeyu Lin
    • 1
    • 2
  • Wenbin Li
    • 1
    • 2
  • Heyun Zhang
    • 1
    • 2
  • Wei Wu
    • 1
    • 3
  • Yaorong Peng
    • 1
    • 2
  • Yunjie Zeng
    • 1
    • 4
  • Yunle Wan
    • 5
  • Jie Wang
    • 1
    • 2
  • Nengtai Ouyang
    • 1
    • 4
  1. 1.Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  3. 3.Breast Tumor Center, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  4. 4.Department of Pathology, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  5. 5.Department of Hepatobiliary Surgery, The Sixth Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina

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