Fibroblast growth factor 7 (FGF7) is a mesenchyme-specific heparin-binding growth factor that binds FGF receptor 2 (FGFR2) to regulate numerous cellular and physiological processes. FGF7/FGFR2 signal is associated with gastric cancer progression. In the present study, we investigated the molecular mechanism by which FGF7/FGFR2 promotes invasion and migration in human gastric cancer. We first demonstrated that increased FGFR2 expression in human gastric cancer tissues was significantly associated with tumor depth and clinical stage in human gastric cancer tissues. Thrombospondin 1 (THBS1) is an extracellular glycoprotein that plays multiple roles in cell-matrix and cell-cell interactions. Increased expression of THBS1 significantly correlated with tumor differentiation. FGFR2 and THBS1 expression were both increased in cancer tissues as compared with adjacent normal tissues and their expression was positively correlated. In vitro, FGF7 stimulation of cell invasion and migration was partially suppressed by the FGFR2 knockdown. In addition, FGF7/FGFR2 upregulated THBS1, and cell invasion and migration were decreased by knockdown of THBS1. Furthermore, the PI3K/Akt/mTOR signaling pathway was predominantly responsible for FGF7/FGFR2-induced THBS1 upregulation. Taken together, our data suggest that FGF7/FGFR2/THBS1 is associated with the regulation of invasion and migration in human gastric cancer.

Although multidisciplinary treatment is widely applied in colorectal cancer (CRC), the prognosis of patients with advanced CRC remains poor. Immunotherapy blocking of programmed cell death ligand 1 (PD-L1) is a promising approach. Binding of the transmembrane protein PD-L1 expressed by tumor cells or tumor microenvironment cells to its receptor programmed cell death 1 (PD-1) induces immunosuppressive signals and reduces the proliferation of T cells, which is an important mechanism of tumor immune escape and a key issue in immunotherapy. However, the regulation of PD-L1 expression is poorly understood in CRC. Fibroblast growth factor (FGF) receptor (FGFR) 2 causes the tyrosine kinase domains to initiate a cascade of intracellular signals by binding to FGFs and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. In this study, we showed that PD-L1 and FGFR2 were frequently overexpressed in CRC, and FGFR2 expression was significantly associated with lymph node metastasis, clinical stage, and poor survival. In the current study, PD-L1 expression was positively correlated with FGFR2 expression in CRC. Tumor-derived–activated FGFR2 induced PD-L1 expression via the JAK/STAT3 signaling pathway in human CRC cells (SW480 and NCI-H716), which induced the apoptosis of Jurkat T cells. FGFR2 also promoted the expression of PD-L1 in a xenograft mouse model of CRC. The results of our study reveal a novel mechanism of PD-L1 expression in CRC, thus providing a theoretical basis for reversing the immune tolerance of FGFR2 overexpression in CRC.

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis. [Cancer Res 2009;69(8):3397-404]