Leptin-mediated regulation of MT1-MMP localization is KIF1B dependent and enhances gastric cancer cell invasion
Authors: Huanhuan Cheng
Xun Qu
Xin Zhang
Lutao Du
Zewu Li
Yongmei Yang
Juan Li
Chuanxin Wang
Zhaogang Dong
Xiaofei Xu
Hui Liu
Lili Wang
Journal: Carcinogenesis (2013)
Discipline: CLINICAL MEDICINE
Keywords: Leptin; Gastric cancer; Invasion; MT1-MMP; KIF1B
Affiliations: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.

Abstract:  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. 

Retracted: No

PubPeer comments:
 Figs 6(c),(d).  Transwell assay; upregulated RKIP expression significantly inhibited the invasion ability of U251 and U87 cell lines . Fig 7(c),(d) are U251 and U87 respectively, I think. ![file] Two panels of 6(d) and 7(d) overlap: brown rectangles. Panels of 7(c) and (d) overlap: dark blur rectangles. Colored rectangles also mark overlaps with [Li et al (2016)] , Figs 3B, 6B.  ...Transwell assay were performed to determine cell ... invasion in glioma U251 and U87 cell transfected with miR-200b mimic or scramble miR mimic ;  ...Transwell assay were performed to determine cell ... invasion in glioma U251 and U87 cell transfected with miR-200b mimic, or co-transfected with miR-200b mimic and ZEB2 plasmid . ![] Given the later reappearance of the images, can the authors check which specific treatments are represented here? ,