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1. High co-expression of the SDF1/CXCR4 axis in hepatocarcinoma cells is regulated by AnnexinA7 in vitro and in vivo

Author

Jingwen Wang, Yuhong Huang, Jun Zhang, Boyi Xing, Wei Xuan, Honghai Wang, He Huang, Jiayu Yang, and Jianwu Tang

Subjects
SDF1, CXCR4, AnnexinA7, VEGFC/D-VEGFR3/NRP2, Hepatocarcinoma, Medicine, Cytology, QH573-671
Abstract

Abstract Background SDF1/CXCR4 and AnnexinA7 play important roles in many physiological and pathological conditions, but the molecular association between them in cancer cells has not been studied thus far. Methods The expression changes of SDF1/CXCR4 were detected by gene transcriptome sequencing, qRT-PCR, Western blotting, cytoimmunofluorescence and immunohistochemistry in mouse hepatocarcinoma F/P cells, AnnexinA7 downregulated expression F (FA7DOWN) cells, AnnexinA7 overexpression P (PA7UP) cells, AnnexinA7 unrelated sequence F (FSHUS) cells, empty vector P (PNCEV) cells and normal liver cells in vitro and in vivo. Results SDF1 and CXCR4 were co-expressed in hepatocarcinoma cells. SDF1 was localized mainly in the cytoplasm of cells, while CXCR4 was mainly localized in the cell membrane. Both in vitro and in vivo, expression levels of SDF1/CXCR4 in F and P cells were higher than in normal liver cells, and expression levels of SDF1/CXCR4 in F cells with high lymphatic metastatic potential were higher than those in P cells with low lymphatic metastatic potential. Expression of SDF1 was higher than that of CXCR4 in P cells and normal liver cells, while expression of CXCR4 was higher than that of SDF1 in F cells. Expression levels of SDF1/CXCR4 were completely consistent with AnnexinA7 regulation. After the AnnexinA7 gene was downregulated or upregulated, expression levels of SDF1/CXCR4 in FA7DOWN/PA7UP cells were lower or higher than those in FSHUS/PNCEV cells. Furthermore, CXCR4 was more sensitively modulated by AnnexinA7 regulation than SDF1. Conclusions High co-expression of SDF1/CXCR4 is a molecular characteristic of hepatocarcinoma cells, especially those with high lymphatic metastatic potential. AnnexinA7 positively regulates expression levels of SDF1/CXCR4, in particular CXCR4, and AnnexinA7 is a functional regulator of SDF1/CXCR4.

Published
2018
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2. NRP-2 in tumor lymphangiogenesis and lymphatic metastasis

Author

Boyi Xing, Jiayu Yang, He Huang, Jianwu Tang, Jun Zhang, Yuhong Huang, Wei Xuan, Jingwen Wang, and Honghai Wang

Subjects
0301 basic medicine, Cancer Research, government.form_of_government, medicine.medical_treatment, Biology, Targeted therapy, Metastasis, 03 medical and health sciences, Semaphorin, Neoplasms, medicine, Animals, Humans, Lymphangiogenesis, Receptor, Endothelial Cells, medicine.disease, Neuropilin-2, Gene Expression Regulation, Neoplastic, Lymphatic Endothelium, 030104 developmental biology, Oncology, Tumor progression, Lymphatic Metastasis, Disease Progression, government, Cancer research, Axon guidance
Abstract

Neuropilin-2 (NRP-2) not only functions as a receptor for semaphorins, a family of neural axon guidance factors, but also interacts with VEGFs, a family of vascular endothelial growth factors. As an independent receptor or a co-receptor, NRP-2 binds to ligands VEGF-C/D, activates the VEGF-C/D-NRP-2 signaling axis, and further regulates lymphangiogenesis-associated factors in both lymphatic endothelial cells (LECs) and some tumor cells during tumor progression. Via VEGF-C/D-NRP-2 axis, NRP-2 induces LEC proliferation, reconstruction and lymphangiogenesis and subsequently promotes tumor cell migration, invasion and lymphatic metastasis. There are similarities and differences among NRP-1, NRP-2 and VEGFR-3 in chemical structure, ligand specificity, chromosomal location, soluble protein forms, cellular functions and expression profiles. High expression of NRP-2 in LECs and tumor cells has been observed in different anatomic sites, histological patterns and progression stages of various tumors, especially during tumor lymphangiogenesis and lymphatic metastasis, and therefore the NRP-2 and VEGF-C/D-NRP-2 axis are closely related to tumor development, progression, invasion, and metastasis. In addition, it is important for prognosis of tumor. The studies on NRP-2 targeted therapy have recently achieved some successes, utilizing NRP-2 blocking antibodies, NRP-2 inhibitory peptides, soluble NRP-2 antagonists, small molecule inhibitors and various NRP-2 gene therapeutic strategies.

Published
2018

3. A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness

Author

Masaharu Seno, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Yuki Katsura, Hiroaki Sato, Hajime Kashima, Yuehua Chen, Akihiro Matsukawa, Takuya Kato, Boyi Xing, Tomonari Kasai, Toru Narusaka, Satoshi Komoto, Shunsuke Kagawa, Hiroshi Tazawa, Takayuki Ninomiya, Toshiyoshi Fujiwara, and Yasuhiro Shirakawa

Subjects
cancer stem cells, 0301 basic medicine, Homeobox protein NANOG, Cancer Research, medicine.medical_treatment, lcsh:RC254-282, Article, combination therapy, Targeted therapy, stemness, 03 medical and health sciences, iron, 0302 clinical medicine, SOX2, Cancer stem cell, Combination cancer therapy, medicine, Induced pluripotent stem cell, Chemistry, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Stem cell
Abstract

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

Published
2019

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