Insulin-like growth factor-1 receptor induces immunosuppression in lung cancer by upregulating B7–H4 expression through the MEK/ERK signaling pathway

Zhao, Zhiming; Zhang, Ningyue; Li, Anqi; Zhou, Bin; Chen, Yali; Chen, Shaomu; Huang, Moli; Wu, Fengying; Zhang, Liang

doi:10.1016/j.canlet.2020.04.013

Cited by 18 publications

(8 citation statements)

References 60 publications

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“…The upregulation of B7-H4 also contributes to the progression and metastasis of different cancers. For example, B7-H4 upregulation induces immune escape of lung cancer [ 42 ] and non-small cell lung cancer cells [ 43 ] through MEK/ERK and PD-1/Stat3 signaling pathways. B7-H4 overexpression promotes the metastasis of bladder cancer cells through Nuclear Factor-kappa B signaling [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

B7 family member H4 induces epithelial-mesenchymal transition and promotes the proliferation, migration and invasion of colorectal cancer cells

et al. 2021

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Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract, which has the second highest incidence among gastrointestinal tumors. At present, due to the limitations of current CRC treatment strategies, there is an urgent need for developing more effective therapies. B7 family member H4 (B7-H4) is associated with the progression of a wide spectrum of cancers, but its functional role in CRC is unknown. The purpose of this study is to clarify the role of B7-H4 in CRC and the underlying mechanisms in controlling the progression of CRC. Our data showed that B7-H4 expression in CRC tissues and cell lines was significantly upregulated as compared with normal tissues and normal cell lines. High B7-H4 expression was correlated with a poor prognosis of CRC patients. B7-H4 overexpression promoted the proliferation and invasion of CRC cells, which could be suppressed by Wnt signaling inhibitor. In a mouse xenograft model, silencing B7-H4 suppressed tumor growth and epithelial–mesenchymal transition (EMT) of CRC cells. Collectively, our study demonstrated the oncogenic roles of B7-H4 in regulating the proliferation, EMT as well as the migration of CRC cells through Wnt signaling pathway. The heightened expression of B7-H4 could serve as a prognostic marker for CRC patients.

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Section: Discussionmentioning

confidence: 99%

B7 family member H4 induces epithelial-mesenchymal transition and promotes the proliferation, migration and invasion of colorectal cancer cells

et al. 2021

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“…In human lung cancer, tumor-associated macrophages secrete TNF-α, IL-10, and IFN-γ, which induce B7-H4 expression in lung cancer cells [ 52 ]. Our previous study revealed that B7-H4 can be upregulated by IGF1R activation through the MEK/ERK1/2 signaling pathway in lung cancer [ 53 ]. In multiple myeloma, hypoxia-inducible factor-1α (HIF-1α) can bind to the B7-H4 promoter and induce B7-H4 expression [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

B7-H4 expression is upregulated by PKCδ activation and contributes to PKCδ-induced cell motility in colorectal cancer

Zhou

Zhao

et al. 2022

Cancer Cell Int

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Introduction B7-H4 is overexpressed in colorectal cancer (CRC) and plays an important role in tumor growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Here, we investigated whether protein kinase C δ (PKCδ) regulates the expression of B7-H4 in CRC. Methods By using immunohistochemical (IHC) and immunofluorescence (IF) staining, we analyzed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumor samples and determined the clinical significance of the expression patterns. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression, and xenograft-bearing mice were treated with rottlerin to monitor the expression of B7-H4 and tumor metastasis. Results The B7-H4 expression level was significantly correlated with the p-PKCδ level (r = 0.378, P < 0.001) in tumor tissues. Coexpression of p-PKCδ and B7-H4 was significantly associated with moderate/poor differentiation (P = 0.024), lymph node metastasis (P = 0.001) and advanced Dukes’ stage (P = 0.002). Western blot analysis showed that Phorbol-12-Myristate-13-Acetate (TPA) increased B7-H4 expression in a concentration-dependent manner and that rottlerin abrogated the TPA-induced increase in B7-H4 expression. The protein levels of B7-H4 and p-STAT3 were significantly reduced by a PKCδ-specific siRNA. Moreover, the STAT3 inhibitor cryptotanshinone significantly decreased the B7-H4 protein level in CRC cells. Knockdown of B7-H4 or PKCδ suppressed cell migration and motility. Rottlerin also inhibited B7-H4 expression and tumor metastasis in vivo. Conclusion The B7-H4 expression level is significantly correlated with the p-PKCδ level and tumor metastasis in CRC samples. B7-H4 expression is upregulated by STAT3 activation via PKCδ and plays roles in PKCδ-induced cancer cell motility and metastasis, suggesting that the PKCδ/STAT3/B7-H4 axis may be a potential therapeutic target for CRC.

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“… 22 The MEK/ERK signaling pathway is also involved in the insulin-like growth factor-1 receptor-induced immunosuppression in lung cancer. 23 FLOT2 has been shown to modulate MEK/ERK pathway activation in cancers. 24 , 25 FLOT2 has also been found to modulate the AKT pathway in glioma.…”

Section: Discussionmentioning

confidence: 99%

FLOT2 Promotes the Proliferation and Epithelial-mesenchymal Transition of Cervical Cancer by Activating the MEK/ERK1/2 Pathway

Li¹,

Dou²

2022

Balkan Med J

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Background: As prevalent cancer in women, approximately 569,847 cases of cervical cancer occur every year. Aims: This study aimed to explore the role of FLOT2 and its related mechanism in the development of cervical cancer. Study Design: Cell culture study and animal experimentation. Methods: Quantitative reverse-transcription polymerase chain reaction PCR and Western blot analysis were performed to evaluate the expression of FLOT2. Flow cytometry was applied for the evaluation of cell apoptosis. Cell Counting Kit-8 and colony formation were utilized for proliferation measurement. Cervical cancer mice model was employed to measure the role of FLOT2 in vivo. Results: FLOT2 mRNA and protein levels were dramatically elevated ( P < 0.001) in cervical cancer cell line HcerEpic cells. The cell viability and proliferation of cervical cancer cells were enhanced ( P < 0.01) by overexpression of FLOT2 and reduced ( P < 0.01) by FLOT2 downregulation. In addition, FLOT2 overexpression elevated ( P < 0.01) the cell migration abilities of cervical cancer cells, whereas its depletion inhibited ( P < 0.01) the cell migration abilities. Moreover, the protein expression of epithelial-mesenchymal transition markers including Vimentin, N-cadherin, and E-cadherin were assessed, and the results showed enhanced Vimentin and N-cadherin levels ( P < 0.05) by FLOT2 upregulation and declined ( P < 0.01) by FLOT2 downregulation. FLOT2 upregulation reduced ( P < 0.05) the level of E-cadherin protein, whereas FLOT2 suppression attenuated this effect ( P < 0.05). Furthermore, FLOT2 increased ( P < 0.05) p-MEK/MEK, p-ERK1/2/ERK1/2, and p-AKT/AKT levels to activate the MEK/ERK1/2 and AKT pathways in cervical cancer. Finally, our results indicated that FLOT2 inhibited ( P < 0.001) cervical cancer growth in vivo. Conclusion: FLOT2 aggravates the proliferation and epithelial-mesenchymal transition of cervical cancer by activating the MEK/ERK1/2 and AKT pathways.

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Insulin-like growth factor-1 receptor induces immunosuppression in lung cancer by upregulating B7–H4 expression through the MEK/ERK signaling pathway

Cited by 18 publications

References 60 publications

B7 family member H4 induces epithelial-mesenchymal transition and promotes the proliferation, migration and invasion of colorectal cancer cells

B7 family member H4 induces epithelial-mesenchymal transition and promotes the proliferation, migration and invasion of colorectal cancer cells

B7-H4 expression is upregulated by PKCδ activation and contributes to PKCδ-induced cell motility in colorectal cancer

FLOT2 Promotes the Proliferation and Epithelial-mesenchymal Transition of Cervical Cancer by Activating the MEK/ERK1/2 Pathway

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