Study on the Expression and Clinical Significances of Lewis y Antigen and Integrin αv, β3 in Epithelial Ovarian Tumors

Wang, Yifei; Liu, Juanjuan; Lin, Bei; Wang, Changzhi; Li, Quanrong; Liu, Shuice; Yan, Limei; Zhang, Shulan; Iwamori, Masao

doi:10.3390/ijms12063409

Cited by 24 publications

(18 citation statements)

References 19 publications

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“…αvβ3 is highly expressed by different ovarian cancer cell lines 9,11 and by primary tissue samples from ovarian cancer patients, 12,13 correlating with disease prognosis. 8,15 Moreover, independently of the αvβ3 expression in the primary tumor, a recent report indicated that the overwhelming majority of tumor vessels in ovarian carcinomas express this receptor, 12 signifying relevance to anti-angiogenic therapeutic strategies. The targeting of αvβ3 in ovarian cancer has been emphasized in mouse models, wherein αvβ3 inhibition improved survival 11,50-53 and the response to therapy correlated with αvβ3 expression level.…”

Section: Discussionmentioning

confidence: 98%

“…12,13 A correlation between the expression of αvβ3 and ovarian tumor progression has been reported. 8,14,15 Independently of the αvβ3 expression in the primary tumor, the overwhelming majority of tumor vessels in ovarian carcinomas express this receptor. 12 Besides its function in ovarian cancer metastasis, αvβ3 has been reported to have a role in ovarian tumor growth in vivo 11 and in vitro.…”

Section: Introductionmentioning

confidence: 99%

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The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

et al. 2015

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Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvβ3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

et al. 2015

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“…The degree of integrin αvβ3 expression has been shown to link with disease prognosis [27, 31]. In addition, there is overexpression of αvβ3 in blood vessels supporting ovarian carcinomas [29], suggesting integrin αvβ3 contributes to angiogenesis and metastasis of ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells

et al. 2016

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Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvβ3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10−7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or β3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.

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“…Many studies have confirmed that carbohydrate antigens on the cell surface are closely related to integrins. In our previous work, we have found that as a part of the integrin αvβ3 structure, Lewis y antigen expression is related to the degree of invasiveness of ovarian cancer [6]. Here we use immunohistochemistry to further study the expression of Lewis y antigen and integrin αvβ3 in tissue specimens from patients with chemotherapy resistant or sensitive ovarian cancer and analyze how the expression of these molecules correlates with chemotherapy resistance and the resulting clinical significance.…”

Section: Introductionmentioning

confidence: 99%

Expression of Lewis y antigen and integrin αv, β3 in ovarian cancer and their relationship with chemotherapeutic drug resistance

Gao

Liu

et al. 2013

J Exp Clin Cancer Res

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ObjectiveThis study investigates the expression of Lewis y antigen, integrin αv, β3 in epithelial ovarian cancer tissues. We further evaluate the relationship between their expression and chemotherapy resistance of ovarian cancer and its possible clinical significance.MethodsTissues of 92 patients with ovarian cancer meeting the inclusion criteria with complete follow-up data were enrolled and divided into chemotherapy resistant group and sensitive group. The expression and relationship of Lewis y antigen and integrin αv, β3 are assessed in paraffin sections using immunohistochemistry and double-labeling immunofluorescence method. Multivariate logistic regression analysis was used to investigate the relationship between age, clinical stage, differentiation, histologic subtype, Lewis y antigen and integrin αv, β3 expression in ovarian cancer patients.ResultsThe expression rates of Lewis y antigen and integrin αv in the resistant group, significantly higher than the rates found in the sensitive group (p <0.05). Multivariate analysis showed that the expression of Lewis y antigen, integrin αv and ovarian cancer’s clinical stage were independent, drug resistance-related risk factors. The expression levels of Lewis y antigen and integrin αv, β3 were positively correlated with each other.ConclusionsA close correlation between Lewis y antigen, integrin αv, β3 and ovarian cancer was observed. Lewis y antigen can influence the biological behavior of a tumor cell as an important composition of integrin αv, β3 by some signal pathway. And the expression of Lewis y antigen, integrin αv and ovarian cancer’s clinical stage are both independent, drug resistance-related risk factors.

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Study on the Expression and Clinical Significances of Lewis y Antigen and Integrin αv, β3 in Epithelial Ovarian Tumors

Cited by 24 publications

References 19 publications

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells

Expression of Lewis y antigen and integrin αv, β3 in ovarian cancer and their relationship with chemotherapeutic drug resistance

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