Leptin-mediated regulation of MT1-MMP localization is KIF1B dependent and enhances gastric cancer cell invasion.
Leptin overexpression is closely correlated with gastric cancer (GC) invasion, but its exact effect and the underlying mechanism in tumorigenesis remain poorly understood. Membrane type 1-matrix metalloproteinase (MT1-MMP), a surface-anchored 'master switch' proteinase, is overexpressed and plays crucial roles in tumor invasion. Here, we characterized the influence of leptin on the generation and surface localization of MT1-MMP in GC and elucidated its molecular mechanisms. Our results revealed that leptin promoted GC cell invasion in vitro by upregulating MT1-MMP expression. Furthermore, cell surface biotinylation assay and flow cytometry demonstrated that the surface expression of MT1-MMP was also enhanced by leptin, and knockdown of kinesin family member 1B (KIF1B, a microtubule plus end-directed monomeric motor protein) by small interference RNA inhibited this process. Notably, coimmunoprecipitation analysis indicated that leptin enhanced the interaction of MT1-MMP with KIF1B in a time-dependent manner, which consequently contributed to GC cell invasion. Moreover, leptin increased MT1-MMP or KIF1B expression by the protein kinase B (AKT) pathway and extracellular signal-regulated kinase 1/2 partially participated in this process. However, only AKT was implicated in the leptin-mediated membrane localization of MT1-MMP. Immunohistochemistry analysis revealed that leptin, MT1-MMP and KIF1B are overexpressed in GC tissues, and they positively correlated with clinical stage and lymph node metastasis. These observations indicate that this regulatory network exists in vivo. Taken together, our findings suggest that leptin is an effective intracellular stimulator of MT1-MMP and that leptin-enhanced cell surface localization of MT1-MMP is dependent on KIF1B, which consequently plays a critical role in GC invasion.
Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.
Zhaogang
Z
Dong
Xiaofei
X
Xu
Lutao
L
Du
Yongmei
Y
Yang
Huanhuan
H
Cheng
Xin
X
Zhang
Zewu
Z
Li
Lili
L
Wang
Juan
J
Li
Hui
H
Liu
Xun
X
Qu
Chuanxin
C
Wang
D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation
C091053:KIF1B protein, human; D020738:Leptin; D051057:Proto-Oncogene Proteins c-akt; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D016547:Kinesins