Sema3E/Plexin-D1 Mediated Epithelial-to-Mesenchymal Transition in Ovarian Endometrioid Cancer

Tseng, Chun Hsien; Murray, Karl D.; Jou, Mu Fan; Hsu, Su Ming; Cheng, Hwai-Jong; Huang, Pei‐Hsin

doi:10.1371/journal.pone.0019396

Cited by 57 publications

(61 citation statements)

References 50 publications

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“…S9, A and B). In addition, nuclear localization of Snail-1, an EMT marker and a downstream effector of PlxnD1 (15), was decreased in SEMA3D knockdown cells in response to transforming growth factor–β [TGF-β, an inducer of EMT (4)] (fig. S10), further suggesting that the role of Sema3D in PDA invasion and EMT-associated migration is likely mediated by PlxnD1.…”

Section: Resultsmentioning

confidence: 99%

Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

et al. 2015

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Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin–plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive and metastatic potential in culture and in mice. However, restoring Sema3D in AnxA2-null cells did not entirely rescue metastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively low Sema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.

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Section: Resultsmentioning

confidence: 99%

Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

et al. 2015

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“…Real-time PCR analysis was used to quantify mRNA or micro-RNA as previously described [6]. Primers used were detailed in Supplementary Materials and methods.…”

Section: Methodsmentioning

confidence: 99%

SOX4 Transcriptionally Regulates Multiple SEMA3/Plexin Family Members and Promotes Tumor Growth in Pancreatic Cancer

et al. 2012

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Semaphorin signaling through Plexin frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. Such concomitant expression of these SEMA3/Plexin family members is not a result of gene amplification, but (at least partially) from increased gene transcription activated by SOX4 de novo expressed in PDAC. Via chromatin-immunoprecipitation, luciferase promoter activity assay and electrophoresis mobility shift assay, SOX4 is demonstrated to bind to the consensus site at the promoter of each SEMA3 and Plexin gene to enhance transcription activity. Conversely, RNAi-knockdown of SOX4 in PDAC cell lines results in decreased expression of SEMA3/Plexin family members and is associated with restricted tumor growth both in vitro and in SCID mice. We further demonstrate that SOX4 levels parallel with the summed expression of SEMA3/Plexin family members (P = 0.033, NPar Kruskal-Wallis one-way analysis), which also correlates with poor survival in human PDAC (P = 0.0409, Kaplan-Meier analysis). Intriguingly, miR-129-2 and miR-335, both of which target SOX4 for degradation, are co-repressed in human PDAC cases associated with up-regulated SOX4 in a statistically significant way. In conclusion, we disclose a miR-129-2(miR-335)/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer.

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“…Semaphorins are not only involved in the developing nervous system, but are also expressed in a wide range of non-neural cells and modulate numerous physiological and pathological processes [6–9]. Some members of class 3 semaphorins (e.g., Sema3C, Sema3E) are up-regulated in some types of cancers [10, 11]. However, some class 3 semaphorins members also have tumor suppressor activity.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of semaphorin 3A promotes tumor progression and predicts poor prognosis in hepatocellular carcinoma after curative resection

Zhou

et al. 2016

Oncotarget

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The semaphorins were originally identified as having roles as guidance cues during neural development. Class 3 semaphorins are involved in cancer progression. However, the roles of class 3 semaphorins in hepatocellular carcinoma (HCC) are unknown. We examined the expression levels of class 3 semaphorins in HCC cell lines with different metastatic potential and in carcinoma tissue samples. The results indicated that Semaphorin 3A expression was up-regulated in metastatic cell lines and in samples from patients with tumor recurrence. Cell functional studies revealed that Semaphorin 3A promoted HCC cell proliferation, migration, and invasion. Animal studies indicated that Semaphorin 3A overexpression enhanced tumor growth and lung metastasis. Semaphorin 3A also acted as a chemoattractant involved in direct recruitment of macrophages in vitro, and facilitated tumor-associated macrophage (TAM) infiltration in vivo. Multivariate analysis revealed that Semaphorin 3A expression alone, or combined with the number of TAMs, can be an independent predictor for overall survival time and time to recurrence. Overall, the results suggested that Semaphorin 3A increased TAM infiltration and promoted HCC progression. Semaphorin 3A expression alone, or combined with the number of TAMs, is a new prognostic factor and potential target for the treatment of HCC.

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Sema3E/Plexin-D1 Mediated Epithelial-to-Mesenchymal Transition in Ovarian Endometrioid Cancer

Cited by 57 publications

References 50 publications

Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

SOX4 Transcriptionally Regulates Multiple SEMA3/Plexin Family Members and Promotes Tumor Growth in Pancreatic Cancer

Overexpression of semaphorin 3A promotes tumor progression and predicts poor prognosis in hepatocellular carcinoma after curative resection

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