SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C

Liu, Dan; Li, Li; Zhang, Xiaoxue; Wan, Dongyi; Xi, Bixin; Hu, Zheng; Ding, Wencheng; Zhu, Da; Wang, Xiaoli; Wang, Wei; Feng, Zuo-Hua; Wang, Hui; Ma, Ding; Gao, Qinglei

doi:10.1158/0008-5472.can-13-3598

Cited by 82 publications

(92 citation statements)

References 49 publications

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“…However, the producers of lymphangiogenic factors are primarily reported to be tumor cells, mesenchymal cells, and immunocytes (3,29,35,36). For instance, oncogenes such as RAS, MYC, and SIX1 lead to the increased expression of lymphangiogenic factors, including members of the VEGF, FGF, and PDGF families (37)(38)(39). So far, it has not been demonstrated whether tumor LECs secret the factor(s) that can regulate tumor lymphangiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Wei

Yang

Liu

et al. 2017

Clinical Cancer Research

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Purpose: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis.Experimental Design: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs.Results: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumorassociated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells.Conclusions: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Wei

Yang

Liu

et al. 2017

Clinical Cancer Research

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“…Therefore, Six1 is necessary for TGF-β to induce increased expression of the VEGF-C gene (41). In addition, overexpression of Six1 significantly enhances the activity of the cyclin D1 promoter in pancreatic cancer and promotes cell cycle progression and proliferation (42).…”

Section: A B Cmentioning

confidence: 99%

Six1 expression is associated with a poor prognosis in patients with glioma

Zhang

2017

Oncology Letters

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Abstract. Glioma is the most common human brain cancer and has poor prognosis. Messenger RNA profiling identified that sineoculis homeobox homolog 1 (Six1) is dysregulated in glioma tumor progenitor cells from glial progenitor cells isolated from normal white matter. However, the expression and role of Six1 in glioma remains unclear. The purpose of the present study was to investigate the expression level of Six1 in glioma tissues and the association between Six1 expression and clinicopathological characteristics and prognosis of gliomas. The Six1 protein was detected by immunohistochemistry in 163 glioma tissues of distinct malignancy grades, and Kaplan-Meier survival analysis was performed to assess the prognosis of the patients. The Six1 protein was stained in 49.1% (80 out of 163) of the glioma tissues, including 34.2% of low-grade [World Health Organization (WHO) I/II] gliomas and 80.8% of high-grade (WHO III/IV) gliomas. Normal brain tissues rarely expressed the Six1 protein. In addition, Six1 expression was significantly associated with WHO grade (P<0.001). According to the log-rank test and Cox regression model, Six1 may be suggested as an independent prognostic factor, in addition to the WHO grade. Overall, Six1 protein expression varies between different grades of glioma and is associated with the WHO grade. Upregulation of Six1 is more frequent in high-grade glioma and is an independent prognostic factor of poor clinical outcome.

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“…The changes in lymphatic vessels can be detected even in early tumor initiation; for instance, the expression of vascular endothelial growth factor C (VEGF-C), a key promoter of lymphangiogenesis, is enhanced at this stage. SIX1 promotes lymphangiogenesis and lymphatic metastasis by upregulating VEGF-C expression [65, 66]. SIX1 transcriptionally activates VEGF-C [65], and overexpression of SIX1 in tumor cells may abrogate the inhibitory effect of TGF-β on lymphangiogenesis by upregulating VEGF-C [66].…”

Section: The Rdgn In Tumor Initiation and Progressionmentioning

confidence: 99%

“…SIX1 promotes lymphangiogenesis and lymphatic metastasis by upregulating VEGF-C expression [65, 66]. SIX1 transcriptionally activates VEGF-C [65], and overexpression of SIX1 in tumor cells may abrogate the inhibitory effect of TGF-β on lymphangiogenesis by upregulating VEGF-C [66]. Considering that EYA2 is an indispensable coactivator in SIX1-induced TGF-β signal activation [19], EYA2 may participate in promoting lymphangiogenesis in a SIX1-dependent manner.…”

Section: The Rdgn In Tumor Initiation and Progressionmentioning

confidence: 99%

The retinal determination gene network: from developmental regulator to cancer therapeutic target

Kong

Liu

et al. 2016

Oncotarget

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Although originally identified for its function in Drosophila melanogaster eye specification, the Retinal Determination Gene Network (RDGN) is essential for the development of multiple organs in mammals. The RDGN regulates proliferation, differentiation and autocrine signaling, and interacts with other key signaling pathways. Aberrant expression of RDGN members such as DACH, EYA and SIX contributes to tumor initiation and progression; indeed, the levels of RDGN members are clinically prognostic factors in various cancer types. Stimulation or suppression of the activities of these crucial components can block cancer cell proliferation, prevent cancer stem cell expansion and even reverse the EMT process, thereby attenuating malignant phenotypes. Thus, cancer therapeutic interventions targeting RDGN members should be pursued in future studies.

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SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C

Abstract: Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant

Cited by 82 publications

References 49 publications

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Six1 expression is associated with a poor prognosis in patients with glioma

The retinal determination gene network: from developmental regulator to cancer therapeutic target

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