MUC15 inhibits dimerization of EGFR and PI3K-AKT signaling and is associated with aggressive hepatocellular carcinomas in patients.
OBJECTIVE
Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC).


METHODS
We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes.


RESULTS
Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of α-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling.


CONCLUSIONS
Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog.
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Shanghai, China; The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
Ruo-Yu
RY
Wang
Lei
L
Chen
Hai-Yang
HY
Chen
Liang
L
Hu
Liang
L
Li
Han-Yong
HY
Sun
Feng
F
Jiang
Jing
J
Zhao
Gao-Mi-Yang
GM
Liu
Jing
J
Tang
Cai-Yang
CY
Chen
Ying-Cheng
YC
Yang
Yan-Xin
YX
Chang
Hui
H
Liu
Jin
J
Zhang
Yuan
Y
Yang
Gang
G
Huang
Feng
F
Shen
Meng-Chao
MC
Wu
Wei-Ping
WP
Zhou
Hong-Yang
HY
Wang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019281:Dimerization; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D009077:Mucins / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D051058:Oncogene Protein v-akt / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011237:Predictive Value of Tests; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate
C460499:MUC15 protein, human; D009077:Mucins; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt
AKT; EGFR; EMT; ERK; GFP; HCC; HGF; IHC; Liver Cancer; MMP; Mechanism; Mouse Model; OS; PI3K; Prognostic Factor; RTK; TIMP; TTR; epidermal growth factor receptor; epithelial−mesenchymal transition; extracellular regulated kinase; green fluorescent protein; hepatocellular carcinoma; hepatocyte growth factor; immunohistochemistry; mRNA; matrix metallopeptidase; messenger RNA; overall survival; phosphoinositide 3-kinase; receptor tyrosine kinase; time to recurrence; tissue inhibitor of metalloproteinases; v-akt murine thymoma viraloncogene homolog