Plexin-B1 is a target of miR-214 in cervical cancer and promotes the growth and invasion of HeLa cells

Qiang, Ran; Wang, Fang; Shi, Li; Liu, Min; Chen, Shuang; Wan, Hai Ying; Li, Yi Xuan; Li, Xin; Gao, Song; Sun, Bei; Tang, Hua

doi:10.1016/j.biocel.2011.01.002

Cited by 117 publications

(115 citation statements)

References 39 publications

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“…While some studies have shown a downregulation of Plexin-B1 expression in melanoma and renal carcinoma, as well as a correlation between low Plexin-B1 expression levels and poor prognosis in breast carcinoma (33,36,37), others have found higher Plexin-B1 expression levels in cancer tissues as compared with normal control tissues (35,38). In microarray analyses we stratified the data according to expression of ErbB-2.…”

Section: Discussionmentioning

confidence: 99%

ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

Worzfeld¹,

Swiercz²,

Looso³

et al. 2012

J. Clin. Invest.

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Diagnosis of metastatic breast cancer is associated with a very poor prognosis. New therapeutic targets are urgently needed, but their development is hampered by a lack of understanding of the mechanisms leading to tumor metastasis. Exemplifying this is the fact that the approximately 30% of all breast cancers overexpressing the receptor tyrosine kinase ErbB-2 are characterized by high metastatic potential and poor prognosis, but the signaling events downstream of ErbB-2 that drive cancer cell invasion and metastasis remain incompletely understood. Here we show that overexpression of ErbB-2 in human breast cancer cell lines leads to phosphorylation and activation of the semaphorin receptor Plexin-B1. This was required for ErbB-2-dependent activation of the pro-metastatic small GTPases RhoA and RhoC and promoted invasive behavior of human breast cancer cells. In a mouse model of ErbB-2-overexpressing breast cancer, ablation of the gene encoding Plexin-B1 strongly reduced the occurrence of metastases. Moreover, in human patients with ErbB-2-overexpressing breast cancer, low levels of Plexin-B1 expression correlated with good prognosis. Our data suggest that Plexin-B1 represents a new candidate therapeutic target for treating patients with ErbB-2-positive breast cancer. IntroductionMetastatic breast cancer remains essentially incurable, demonstrating the critical need for the understanding of the molecular determinants of breast cancer cell invasion and metastasis. The receptor tyrosine kinase ErbB-2 is overexpressed in about 30% of all breast cancers, and ErbB-2-overexpressing tumors are characterized by high metastatic potential and poor prognosis (1, 2). Several signaling proteins and pathways have been reported to contribute to the metastatic potential of ErbB-2-overexpressing breast cancers (3-5). These include transmembrane proteins such as integrins and EphA2 (6, 7), as well as cytosolic signaling pathways such as those mediated by Ras, Src, or the PI3K/Akt pathway (8-12). However, despite considerable progress, the signaling events mediating cancer cell invasion and metastasis in ErbB-2-overexpressing tumors are still incompletely understood, and therapeutic options for the treatment of ErbB-2-overexpressing breast cancers remain insufficient. Therefore, a better understanding of the molecular mechanisms driving ErbB-2-dependent metastasis is required to develop more effective treatments for this aggressive type of breast cancer.Plexin-B1 belongs to a family of transmembrane receptors that mediate the cellular effects of semaphorins (13). While plexins were described in the context of axon guidance, several recent studies have established them as regulators of organogenesis, the immune system, and cancer (14-16). Plexin-B1 has been shown to interact with ErbB-2 (17). Binding of the Plexin-B1 ligand semaphorin 4D (Sema4D) to Plexin-B1 stimulates the kinase activity of ErbB-2, which leads to phosphorylation of Plexin-B1 at two specific tyrosine residues (18,19). This regulation of ErbB-2 activity via Plexin-B...

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Section: Discussionmentioning

confidence: 99%

ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

Worzfeld¹,

Swiercz²,

Looso³

et al. 2012

J. Clin. Invest.

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“…[7][8][9] In contrast, miR-214 was found to be down-regulated in breast cancer, resulting in increased cell proliferation and invasion. 10 Likewise, low miR-214 expression levels were associated with metastasis and invasion of cervical tumors 11 and it has also been recently described that miR-214 is down-regulated in primary central nervous system lymphomas. 12 In order to investigate the potential involvement of miR-214 in myeloma pathogenesis, we explored the functional role of miR-214 in myeloma cells.…”

Section: Introductionmentioning

confidence: 94%

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

et al. 2012

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“…Contrasting findings regarding the expression profile of Sema4D and the plexin-B family in relation to different types of tumours have also been reported. For example, an increased Sema4D and plexin-B1 expression has also been observed in prostate (25)(26)(27), cervical (28), and breast and ovarian cancers (29). A combined effect of increased plexin-B1 along with c-Met was associated with poor cell differentiation and higher lymph node metastasis.…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor

Malik

Jiang

2015

Oncology Reports

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Abstract. Involvement of semaphorin 4D (Sema4D) and the receptor proteins of the plexins B family (plexin-B1, -B2 and -B3) in solid tumours suggests they play a role in breast cancer. In the present study, the expression of Sema4D and plexin-Bs was examined in a breast cancer cohort. The expression of Sema4D and plexin-Bs was examined in 147 tumours together with 22 normal mammary tissues using quantitative PCR along with clinicopathological patient data, as well as in MCF-7 and MDA-MB-231 cell lines treated with selective oestrogen receptor modulators (SERMs). The expression of Sema4D, plexin-B1 and -B2 was markedly reduced in tumours with local recurrence, compared to the patients that remained disease-free. The reduced Sema4D expression was associated with poorer disease-free survival (median, 111.6 months, 95% CI, 96.5-126.7), compared to the patients with a higher expression (median, 144.0 months; 95% CI, p=0.033). A reduced expression of plexin-B1 was observed in tumours with poorer differentiation and was associated with poorer overall and disease-free survival. No similar association was identified in relation to plexin-B2 and -B3. A higher expression of Sema4D and plexin-B1 was observed in the ERα-positive tumours compared to the ERα-negative tumours. The expression of these molecules was largely regulated in breast cancer cells exposed to SERMs. A decreased expression of Sema4D, plexin-B1 and -B2 was associated with local recurrence and poor prognosis. Response to SERMs indicated potential perspectives of these molecules in clinical assessment and management of diseases. IntroductionBreast cancer is a heterogeneous disease influenced by genetic and environmental factors (1). Tumour metastasis is regulated by a set of non-randomized events, starting from loss of cancer cells adhesion at the primary site, local invasion, intravasation, survival in circulation, extravasation and colonisation at distant sites. The nervous and vascular system share several anatomical and developmental similarities as these systems are combined in neurovascular bundles and in peripheral tissues. Notably, these shared developmental links also assist scientists to speculate the involvement of certain molecules controlling growth and migration of nerves in cancer cell proliferation, differentiation and dissemination (2,3). Apart from acting as axonal guidance cues, the involvement of semaphorins and plexins in altering the cytoskeleton, organization of actin filaments and microtubule networks in non-neural systems has also been observed (4,5).Semaphorins are classified as secreted, transmembrane or glycosylphosphatidylinositol-linked proteins containing a phylogenetically conserved extracellular 'sema' domain. These molecules are further delineated into eight classes, of which classes 3-7 are present in vertebrates (6). Plexins are transmembrane protein receptors for semaphorins grouped further under A to D categories. Previously, the two families were initially identified as axon guidance cues in the nervous system and were la...

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Plexin-B1 is a target of miR-214 in cervical cancer and promotes the growth and invasion of HeLa cells

Cited by 117 publications

References 39 publications

ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor

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