Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance

AlHossiny, Midrar; Luo, Linlin; Frazier, William R.; Steiner, Noriko; Gusev, Yuriy; Kallakury, Bhaskar; Glasgow, Eric; Creswell, Karen; Madhavan, Subha; Kumar, Rakesh; Upadhyay, Geeta

doi:10.1158/0008-5472.can-15-2654

Cited by 83 publications

(90 citation statements)

References 49 publications

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“…Ubiquitination and N-glycosylation have known effects on the immunosuppressive activity of PD-L1 35. Also, increased expression of stem cell antigens Ly6K and Ly6E is reported to facilitate the activation and expression of cytokine-induced PD-L1, subsequently promoting drug resistance 36. The alimentary nutrient apigenin and its essential component luteolin have both been shown to indirectly inhibit interferon (IFN)-γ-induced PD-L1 expression via depression of signal transducer and activator of transcription (STAT) 1 phosphorylation, while not affecting constitutive PD-L1 31…”

Section: Tumor-related Immune Evasionmentioning

confidence: 99%

“…Tregs can protect CTC from immune attack, alleviate the killing capacity of CTLs, and trigger larger quantity of myeloid-derived suppressor cells (MDSCs) 33. Immune infiltration of Tregs is related to clinical prognosis,72 and can be augmented by Ly6E and Ly6K 36. The upregulation of GITR-related protein with Treg-inhibiting activity increases the proliferation, activation, and synthesis of cytokines 49.…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

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Mechanism of immune evasion in breast cancer

Wang¹,

Zhang²,

Song³

et al. 2017

OTT

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Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.

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Section: Tumor-related Immune Evasionmentioning

confidence: 99%

Section: Tumor Microenvironmentmentioning

confidence: 99%

Mechanism of immune evasion in breast cancer

Wang¹,

Zhang²,

Song³

et al. 2017

OTT

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“…The potential mechanism was then analyzed. It has been previously shown that LY6E could downregulate tumor-suppressor proteins, including phosphatase with tensin homology (PTEN) [33], and E-Cadherin [34], thus promoting cell proliferation and invasion. In this study, we show that LY6E knockdown by LY6E siRNA3 increased expressions of PTEN (increase by 183.4%) and E-Cadherin (increase by 87.1%) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…LY6E is involved in cell signalling transduction, cell adhesion, immune regulation and drug resistance [21, 33, 34, 43]. It is over-expressed in human malignancies, including head and neck squamous cell carcinomas and lung, and oesophageal cancers [21, 33, 34, 43].…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of Lymphocyte Antigen 6 Complex, Locus E in Gastric Cancer Promotes Cancer Cell Growth and Metastasis

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lymphocyte antigen 6 complex, locus E (LY6E) is a member of the lymphostromal cell membrane Ly6 superfamily protein. The present study investigated the clinical significance and potential biological function of LY6E in gastric cancer (GC). Methods: LY6E mRNA and protein expressions in human GC tissues and GC cells were tested. Relationship between LY6E expression and the GC patients’ clinicopathologic characteristics was analyzed. LY6E was silenced by siRNA in the cultured GC cells. Results: The RNA expression microarray profiling assay results demonstrated that LY6E mRNA was significantly increased in multiple human GC tumor tissues. Immunohistochemistry (IHC) staining analysis revealed that 59 of 75 (78.7%) GC specimens were LY6E positive. LY6E over-expression in human GC was correlated with the histology grade, AJCC stage, N classification, lymphatic invasion, and tumor location. Notably, functional LY6E expression was also detected in AGS and other established GC cell lines. LY6E knockdown by targeted-siRNA inhibited AGS cell survival and proliferation. Meanwhile, the LY6E siRNA induced G1-S cell cycle arrest and apoptosis in AGC cells. Additionally, AGC cell migration was also inhibited by LY6E knockdown. Expressions of tumor-suppressing proteins, including PTEN (phosphatase and tensin homolog) and E-Cadherin, were increased in LY6E-silenced AGS cells. Conclusion: LY6E over-expression in GC is potentially required for cancer cell survival, proliferation and migration.

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LY6K depletion modulates TGF‐β and EGF signaling

Park

Park²,

Han

et al. 2023

Cancer Medicine

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Background: Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol-anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) signaling through clathrin-and caveolin-1 (CAV-1)-mediated endocytosis.Methods: Analysis of the TCGA and GTEx dataset were performed to explore the expression and survival of LY6K in cancer patients. Short interfering RNA (siRNA) was used to knockdown the expression of LY6K in human cervical cancer patients. The effect of lack of LY6K on cell proliferation, migration, and invasion was performed, and RT-qPCR and immunoblotting were performed to identify LY6K-affected TGF-β and EGF signaling pathways. Additionally, Immunofluorescence (IF) and transmission electron microscope (TEM) were performed to identify the role of LY6K in CAV-1-and Clathrin-mediated endocytosis.Results: Lymphocyte antigen 6 complex locus K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression-free survival, and disease-free survival. LY6K-depletion in HeLa and SiHa cancer cells suppressed EGF-induced proliferation and TGF-βenhanced migration and invasion. Both TGF-β receptor-I (TβRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TβRI irrespective of the presence of TGF-β; however, LY6K did not bind EGFR. LY6K-depleted cells showed impaired Smad2 phosphorylation upon TGF-β treatment and lower proliferation rates following long-term treatment with EGF. We revealed the atypical movement of TβRI and EGFR from plasma membrane upon ligand stimulation in LY6K-depleted cells and an impaired movement of the endocytic proteins clathrin and CAV-1. Conclusions:Our study demonstrates the key role of LY6K in both clathrin-and CAV-1-mediated endocytic pathways regulated by TGF-β and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival.

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Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance

Cited by 83 publications

References 49 publications

Mechanism of immune evasion in breast cancer

Mechanism of immune evasion in breast cancer

Overexpression of Lymphocyte Antigen 6 Complex, Locus E in Gastric Cancer Promotes Cancer Cell Growth and Metastasis

LY6K depletion modulates TGF‐β and EGF signaling

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