siRNA-mediated silencing of integrin β3 expression inhibits the metastatic potential of B16 melanoma cells

Nasulewicz‐Goldeman, Anna; Uszczyńska, Barbara; Szczaurska-Nowak, Katarzyna; Wietrzyk, Joanna

doi:10.3892/or.2012.1963

Cited by 16 publications

(10 citation statements)

References 44 publications

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“…The inhibition of primary tumor growth observed here was clearly independent of the proangiogenic effects of αvβ3-int expressed in endothelial cells. A decrease in the growth of B16 tumor cells depleted of β3-int was previously described, but the underlying mechanism was not elucidated (45). We conclude that αvβ3-int is a driver of the tumor immune evasion system.…”

Section: Discussionmentioning

confidence: 99%

αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

Vannini

Leoni

Barboni

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin–depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin–depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti–PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

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Section: Discussionmentioning

confidence: 99%

αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

Vannini

Leoni

Barboni

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…β3 integrin has been detected in tumor tissues from patients with melanoma, breast cancer and its expression is particularly pronounced in metastatic tissue (7,25,26). TNBC is a highly aggressive subgroup of breast cancer and currently lacks definite molecular targets for effective targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer

Liu

Zhao

et al. 2016

International Journal of Oncology

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Integrins are adhesion receptors involved in bidirectional signaling and are crucial for various cellular responses during normal homeostasis and pathological conditions, such as cancer progression and metastasis. In the present study, we demonstrated that blockage of β3 integrin-mediated cell- extracellular matrix interactions restrained triple-negative breast cancer (TNBC) growth, and elevated β3 integrin can trigger the rewiring of Erk/Ets-1 signaling pathways, thereby enhancing cell growth and invasion. Ectopic expression of miRNA has been implicated in the deregulation of integrin expression and activity, blocking of cancer tumor development and progression, and acquisition of metastatic phenotype. miR-30a-5p expression has been implicated in the progression of breast cancer. Overexpression of miR-30a-5p suppressed the proliferation, migration and invasion of breast cancer cells. On the contrary, inhibition of miR-30a-5p promoted the proliferation, migration, and invasion of TNBC cells by suppressing the expression of ERK/Ets-1 signal. An inverse correlation was found between the mRNA expressions of miR-30a-5p and β3 integrin in TNBC samples. Furthermore, bioinformatics analysis revealed the putative miR-30 binding sites in the 3'-UTR of β3 integrin. Results of luciferase assay revealed a strong repression of luciferase activity after transfection with miR‑30a-5p and wild-type 3'-UTR of β3 integrin. In TNBC cells, miR-30a-5p promoted an epithelial phenotype and suppressed invasion by specifically targeting β3 integrin subunit to subsequently interdict the β3 integrin/Erk/Ets-1 network.

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“…39,43–45 Integrins modulate breast cancer migration and invasion in multiple ways via a range of signaling pathways. A common integrin signaling molecule is FAK, which has been suggested to play a significant role in tumor formation and metastasis.…”

Section: Discussionmentioning

confidence: 99%

cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells

Spina

Maiolo

Esposito

et al. 2012

BioResearch Open Access

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Breast cancer is one of the most common malignancies and a major cause of cancer death among women worldwide. The high mortality rate associated with breast cancer is mainly due to a propensity of the tumor to metastasize, even if small or undetectable. Given the relevant role of leptin in breast cancer growth and metastasis, novel strategies to counteract biological effects of this obesity-linked cytokine are warranted. Recently, we demonstrated that in MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1/2 and STAT3 phosphorylation in response to leptin. Very surprisingly, this provided evidence that when cAMP levels are increased, leptin drives cells towards apoptosis associated with a marked decrease of Bcl2 protein levels and accompanied by down-regulation of protein kinase A (PKA). The aim of the current study was to investigate the role of cAMP in leptin-associated motility of breast cancer cells. Here we show that cAMP elevation completely prevents leptin-induced migration of MDA-MB-231 breast cancer cells. Interestingly, the inhibition by cAMP-elevating agents of leptin-mediated cell migration is accompanied by a strong decrease of β3 integrin subunit and focal adhesion kinase (FAK) protein levels. Analysis of the underlying cAMP-dependent molecular mechanisms revealed that PKA blockers partly counteract the inhibition of leptin-induced migration and completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue that specifically activates Epac and not PKA has an inhibitory effect on leptin-induced cell migration as well. The present study confirms initial evidence for the efficacy of cAMP elevation against oncogenic effects of leptin, identifies β3 integrin subunit and FAK as proteins strongly down-regulated by cAMP elevation, and suggests that both cAMP/PKA- and cAMP/Epac-dependent pathways are involved in inhibition of leptin-induced migration of MDA-MB-231 breast cancer cells. The potential clinical significance and therapeutic applications of our data are discussed.

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siRNA-mediated silencing of integrin β3 expression inhibits the metastatic potential of B16 melanoma cells

Cited by 16 publications

References 44 publications

αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer

cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells

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