SNX9 determines the surface levels of integrin β1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9

Tanigawa, Kazufumi; Maekawa, Mamoru; Kiyoi, Takeshi; Nakayama, Jun; Kitazawa, Riko; Kitazawa, Sohei; Semba, Kentaro; Taguchi, Tomohiko; Akita, Satoshi; Yoshida, Misao; Ishimaru, Kei; Watanabe, Yuji; Higashiyama, Shigeki

doi:10.1002/jcp.28346

Cited by 23 publications

(20 citation statements)

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“…Recently, sorting nexin 9 (SNX9) regulates invadopodia formation and cell invasion in breast cancer cells [26,27]. SNX9 protein is highly expressed in tumor and tumor-endothelial cells of human CRC tissues [28], suggesting that SNX9 may also function in cell invasion/migration in the epithelial cells of CRCs, in addition to its novel function in angiogenesis of the endothelial cells. Thus, we stained SNX9 in human CRC tissues, and the results showed that high SNX9 expression in CRC cells (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Human Colorectal Cancer Infrastructure Constructed by the Glycocalyx

Tachi

Okada

Matsuhashi

et al. 2019

JCM

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Cancer cells can survive and grow via angiogenesis. An alternative but controversial theory is cancer cells may grow via vasculogenic mimicry (VM), in which the cancer cells themselves construct vessel-like channels that are considered a leading cause of drug resistance. The dynamic functions of the glycocalyx (GCX), a meshwork composed of proteoglycans and glycoproteins that surrounds cell membranes, have been observed in endothelial cells within tumors. However, the actual structural shape formed by the GCX in human patients remains unclear. Here, we visualized the three-dimensional (3D) network structure constructed by bulky GCX in human colorectal cancer (CRC) patients using scanning electron microscopy with lanthanum nitrate staining. The network structure extended throughout the cancer cell nest, opening into capillaries, with a tunnel channel that exhibited a net- and spongy-like ultrastructure. The expression of endothelial and cancer-specific GCX-binding lectins was dramatically increased in the interstitial spaces between cancer cells. Even accounting for the presence of artifacts resulting from sample preparation methods, the intercellular tunnels appeared to be coated with the bulky GCX. Further, this 3D network structure was also observed in the tumors of ApcMin/+ mice. In conclusion, the bulky GCX modifies the network structure of CRCs in human and mice.

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Section: Resultsmentioning

confidence: 99%

Human Colorectal Cancer Infrastructure Constructed by the Glycocalyx

Tachi

Okada

Matsuhashi

et al. 2019

JCM

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“…Several studies have shown that VEGFA‐mediated angiogenesis is the leading factor for the progression of breast cancer, lung cancer, and glioblastoma, providing essential nutrients for increased growth and tumor progression 5,20‐22 . The expression of integrin β1 in endothelial cell is essential for angiogenesis 23 . VEGF can interact with integrin by VEGFR2 and activate the binding function of multiple integrins in both endothelial and tumor cells through the PI3K/AKT pathway 24 .…”

Section: Discussionmentioning

confidence: 99%

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

et al. 2020

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Glioblastoma, also known as glioblastoma multiforme (GBM), is a fast‐growing tumor and the most aggressive brain malignancy. Proteasome subunit beta type‐8 (PSMB8) is one of the 17 essential subunits for the complete assembly of the 20S proteasome complex. The aim of the present study was to evaluate the role of PSMB8 expression in GBM progression and angiogenesis. PSMB8 expression in glioblastoma LN229 and U87MG was knocked down by siRNA or inducible shRNA both in vitro and in vivo. After PSMB8 reduction, cell survival, migration, invasion, angiogenesis, and the related signaling cascades were evaluated. An orthotopic mouse tumor model was also provided to examine the angiogenesis within tumors. A GEO profile analysis indicated that high expression of PSMB8 mRNA in GBM patients was correlated with a low survival rate. In immunohistochemistry analysis, PSMB8 expression was higher in high‐grade than in low‐grade brain tumors. The proliferation, migration, and angiogenesis of human GBM cells were decreased by PSMB8 knockdown in vitro. Furthermore, phosphorylated focal adhesion kinase (p‐FAK), p‐paxillin, MMP2, MMP9, and cathepsin B were significantly reduced in LN229 cells. Integrin β1 and β3 were reduced in HUVEC after incubation with LN229‐conditioned medium. In an orthotopic mouse tumor model, inducible knockdown of PSMB8 reduced the expression of vascular endothelial growth factor (VEGF), VEGF receptor, and CD31 as well as the progression of human glioblastoma. In this article, we demonstrated the role of PSMB8 in glioblastoma progression, especially neovascularization in vitro and in vivo. These results may provide a target for the anti–angiogenic effect of PSMB8 in glioblastoma therapy in the future.

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“…Not surprisingly, the deregulation of SNX9 expression contributes to many human diseases, including Lowe syndrome ( Nandez et al, 2014 ), Chlamydia-induced infection ( Hansch et al, 2020 ), chronic inflammation ( Ish-Shalom et al, 2016 ), and cancer ( Bendris et al, 2016a , b ). As a scaffold, changes in SNX9 expression could result in internal competition for binding partners, disrupting cellular activities, such as cell metastasis and angiogenesis ( Bendris et al, 2016a , b ; Bendris and Schmid, 2017 ; Tanigawa and Maekawa, 2019 ). Of note, recent studies have uncovered the vital role played by SNX9 in the pathogenesis of renal diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Sorting nexin 9 (SNX9) maps to human chromosome 6q25.3 and was first identified for its role in clathrin-mediated endocytosis ( Bendris and Schmid, 2017 ). As a multifunctional protein, SNX9 plays vital roles in diverse endocytic vesicle sorting activities, the regulation of actin polymerization, cell migration and invasion, and cell division ( Soulet et al, 2005 ; Shin et al, 2008 ; Yarar et al, 2008 ; Bendris et al, 2016a ; Tanigawa and Maekawa, 2019 ). However, the expression pattern and potential biological functions of SNX9 during ADPKD remain unclear.…”

Section: Introductionmentioning

confidence: 99%

SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway

Shen

Lü

et al. 2020

Front. Cell Dev. Biol.

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Autosomal dominant polycystic kidney disease (ADPKD) is a complex process, involving the alteration of multiple genes and signaling pathways, and the pathogenesis of ADPKD remains largely unknown. Here, we demonstrated the suppressive role of sorting nexin 9 (SNX9) during ADPKD development. Sorting nexin 9 expression was detected in the kidney tissues of ADPKD patients, for the first time, and SNX9 expression was also detected in Pkd1 knockout (Pkd1 −/−) and control mice. Subsequently, a series of gain-and loss-of-function studies were performed, to explore the biological roles and underlying molecular mechanisms of SNX9 in ADPKD progression. The expression of SNX9 was significantly downregulated in ADPKD patients and Pkd1 −/− mice compared with control individuals and wild-type mice (Pkd1 +/+), respectively. The ectopic expression of SNX9 significantly inhibited ADPKD cell proliferation, renal cyst formation and enlargement, whereas these effects were promoted by SNX9 silencing. Mechanistically, we found that SNX9 interacted directly with yes-associated protein (YAP) and increased the large tumor suppressor kinase 1-mediated phosphorylation of YAP, resulting in the cytoplasmic retention of YAP, the decreased transcriptional activity of the YAP/TEA domain transcription factor 4 complex, and, consequently, the inhibition of Hippo target gene expression and ADPKD development. Taken together, our findings provided novel insights into the role played by SNX9 during ADPKD pathogenesis and may reveal novel therapeutic approaches for ADPKD and related kidney diseases.

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SNX9 determines the surface levels of integrin β1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9

Cited by 23 publications

References 50 publications

Human Colorectal Cancer Infrastructure Constructed by the Glycocalyx

Human Colorectal Cancer Infrastructure Constructed by the Glycocalyx

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway

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