It was demonstrated that Sphingosine kinase 1 (SphK1) promotes tumor progression and confers the malignancy phenotype of colorectal cancer by activating the focal adhesion kinase (FAK) pathway. However, further clarification is required to determine if SphK1 promotes the metastasis of colorectal cancer by inducing epithelial-mesenchymal transition (EMT), and its mechanisms have not been fully elucidated. Immunohistochemistry staining was used to detect protein expression in normal colonic mucosa tissues and colorectal cancer tissues. Cells were transfected to overexpress SphK1, downregulate SphK1 or downregulate FAK. An MTT assay was used to detect the drug toxicity to cells. Transwell and wound healing assays were used to detect cell migration ability. Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the expression of mRNA and protein, respectively. Scanning electron microscopy was used to observe the microvilli and pseudopodia of the cells. The analysis of protein expression in 114 human colorectal cancer tissues demonstrated that the expressions of SphK1, FAK, phosphorylated (p)-FAK, E-cadherin and vimentin were associated with the metastasis of colorectal cancer. Furthermore, the patients with colorectal cancer with SphK1-positive cancer demonstrated poorer prognosis compared with SphK1-negative cancer. FAK knockdown and SphK1 knockdown of human colon cancer RKO cells inhibited the EMT and migrational potency, along with the expression of p-FAK, p-protein kinase B (AKT) and matrix metalloproteinase (MMP)2/9. In contrast, SphK1 overexpression promoted EMT, migrational potency, and the expression of p-FAK, p-AKT and MMP2/9 in HT29 cells. Additionally, the EMT and migrational potency of SphK1-overexpressing HT29 cells was suppressed by a FAK inhibitor, and the expression of p-FAK, p-AKT and MMP2/9 was suppressed by blocking the FAK pathway. In conclusion, SphK1 promoted the migration and metastasis of colon cancer by inducing EMT mediated by the FAK/AKT/MMPs axis.

Systematic chemotherapy is indispensable for gastric cancer patients with advanced stage disease, but the occurrence of chemoresistance drastically limits treatment effectiveness. There is a tremendous need for identifying the underlying mechanism of chemoresistance. NIK‑ and IKKβ‑binding protein (NIBP) (also known as TRAPPC9, trafficking protein particle complex 9) is a regulator of the cytokine‑induced NF‑κB signaling pathway which has been proven to play pivotal roles in the progression of various malignancies. Nevertheless, it is still ambiguous whether NIBP is involved in the chemoresistance of gastric cancer. The aim of the present study was to investigate the effect of NIBP on chemotherapy resistance of gastric cancer (GC) and to research the mechanisms of Ginkgo biloba extract 761 (EGb 761®) on reversing chemoresistence which has been confirmed in our previous study. In the present study, the results of immumohistochemisty revealed that the positive staining rates of NIBP, NF‑κB p65 and NF‑κB p‑p65 in gastric cancer tissues were obviously higher than those in normal tissues. Furthermore, a close correlation was found to exist between the expression of NIBP and NF‑κB p65 (p‑p65) in gastric cancer tissues. Moreover, the overexpression of NIBP was closely related to tumor differentiation, depth of invasion, clinical stage and lymphatic metastasis in gastric cancer. Western blot analysis, real‑time PCR, MTT assay and flow cytometric analysis were performed and the results demonstrated that compared with the gastric cancer SGC‑7901 cells, the expression of NIBP, NF‑κB p65, NF‑κB p‑p65 and mesenchymal marker vimentin were significantly increased in gastric cancer multidrug‑resistant SGC‑7901/CDDP cells, and the epithelial cell marker ZO‑1 was significantly decreased. Meanwhile, it was found that SGC‑7901/CDDP cells were accompanied by spindle‑like mesenchymal appearance and upregulation of stem cell marker CD133 which has been verified to be an upstream regulatory gene of epithelial‑mesenchymal transition (EMT). Further research confirmed that downregulation of NIBP by Ginkgo biloba extract (EGb) 761 EGb 761 suppressed the cis‑diamminedichloroplatinum(II) (CDDP)‑induced NF‑κB signaling pathway, EMT and the expression of CD133 in SGC‑7901 and SGC‑7901/CDDP cells. Altogether, these data indicate that the NIBP‑regulated NF‑κB signaling pathway plays a pivotal role in the chemoresistance of gastric cancer by promoting CD133‑induced EMT.

BackgroundGinkgo biloba extract (EGb761), a standard extract of the Chinese traditional medicine Ginkgo biloba, plays an anti-tumor role in various cancers. However, whether EGb761 is involved in the invasion and metastasis of gastric cancer remains unclear.Material/MethodsIn the current study, cell viability assay, Western blotting, wound-healing assay, Transwell invasion assay, and orthotopic transplantation model were performed to explore the effects of EGb761 on gastric cancer.ResultsIn vitro, the results showed that EGb761 suppressed the proliferation of gastric cancer cells in a dose-dependent manner. Furthermore, the migration and invasiveness were weakened and the protein levels of p-ERK1/2, NF-κB P65, NF-κB p-P65, and MMP2 were decreased by EGb761 or U0126 (an inhibitor of ERK signaling pathway) exposure in gastric cancer cells. Moreover, the combined treatment with EGb761 and U0126 significantly inhibited ERK, NF-κB signaling pathway, and the expression of MMP2 than those of single drug. In vivo, EGb761 inhibited the tumor growth and hepatic metastasis of gastric cancer in the mouse model. Results of immunohistochemistry indicated that the expression of ERK1/2, NF-κB P65 and MMP2 were decreased by EGb761 in the tumor tissues.ConclusionsEGb761 plays a vital role in the suppression of metastasis and ERK/NF-κB signaling pathway in gastric cancer.

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