Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients

Watson, Nicholas; Spendlove, Ian; Madjd, Zahra; McGilvray, Roger; Green, Andrew; Ellis, Ian O.; Scholefield, J H; Durrant, Lindy G.

doi:10.1002/ijc.21510

Cited by 134 publications

(105 citation statements)

References 27 publications

(28 reference statements)

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“…As previously shown, MICA/B protein was detected with different subcellular localization patterns (mainly cytoplasmic) in 58% of samples (Fig. 8A, Table I) (30). A polarized abluminal staining was observed in 71% of well-differentiated tumors, whereas it was not detected in poorly differentiated tumors (Fig.…”

Section: Mica/b Expression Is Lost and Infiltration Of Nkg2d + Lymphosupporting

confidence: 70%

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

López‐Soto

Huergo-Zapico

Galván

et al. 2013

The Journal of Immunology

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Epithelial–mesenchymal transition (EMT) is a morphogenetic process characterized by the acquisition of mesenchymal properties linked with an invasive phenotype and metastasis of tumor cells. NK group 2, member D (NKG2D) is an NK cell–activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain–related molecules A and B (MICA/B) and ULBP1-3. Overexpression of Snail1 and inhibition of glycogen synthase kinase-3β in colorectal tumor cells markedly induced the activity of Sp1 transcription factor, which plays a key role in the upregulation of NKG2DL expression during EMT. The stimulation of MICA/B expression by TGF-β treatment was independent of Sp1, but it involved posttranslational mechanisms mediated by mammalian target of rapamycin pathway. Accordingly, with the increased expression of NKG2DLs, triggering of EMT rendered cancer cells more susceptible to NKG2D-mediated killing by NK cells. In agreement, MICA/B were expressed in vivo in well-differentiated colorectal tumors with retained epithelial characteristics, whereas no expression of MICA/B was detected in poorly differentiated and invasive colorectal tumors that have lost epithelial characteristics. This decrease of MICA/B expression was associated with a dramatic increase of NKG2D+-tumor infiltrating lymphocytes. Overall, our findings indicate that EMT is a relevant checkpoint in the control of tumor progression through NKG2D-mediated immune responses.

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Section: Mica/b Expression Is Lost and Infiltration Of Nkg2d + Lymphosupporting

confidence: 70%

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

López‐Soto

Huergo-Zapico

Galván

et al. 2013

The Journal of Immunology

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“…4,5 NKG2DL, however, are stress-inducible and often found to be expressed on a variety of solid tumors and lymphoproliferative malignancies. [6][7][8][9][10][11][12][13][14][15] Consequently, the expression of both, the NKG2D receptor and its ligands, has a crucial role in immune defense mechanisms against tumor cells by T and NK cells: studies in mice showed that NK and CD8 T cells eliminated NKG2DL-positive tumor cells through the NKG2D receptor. 16,17 It was further shown that NKG2D protected the host from tumor initiation.…”

Section: Introductionmentioning

confidence: 99%

The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

et al. 2010

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Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N ¼ 51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (Po0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA4990 pg/ml (P ¼ 0.014), sMICB4200 pg/ml (P ¼ 0.0001), and sULBP24105 pg/ml (Po0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P ¼ 0.002), sULBP2 (P ¼ 0.002) and ZAP-70 (P ¼ 0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels4105 pg/ml were strongly associated (P ¼ 0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression.

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“…Upregulation of the expression of MIC genes in response to biological stress is recognized by the NKG2D activating receptors in NK cells, ab T and cd T lymphocytes acting as a mechanism of immunosurveillance [17][18][19]. Engagement of NKG2D by MIC costimulates antigenspecific cytolytic and cytokine responses in CD8ab T cells under suboptimal TCR stimulation conditions, such as the down-modulation of MHC-I frequently associated with tumors but NKG2D alone can also trigger cd T and NK cells in a TCR-independent manner [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

et al. 2007

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MHC class I-related genes A/B (MICA/B) are ligands of the NKG2D receptor expressed on T and NK cells. Their expression is highly restricted in normal tissues, but is upregulated in tumoral and infected cells. We show that the minimal promoter of both genes contains a CCAAT box, which binds to NF-Y, and a GC box, which binds to Sp1, Sp3 and Sp4. We also demonstrate that MICB promoter is polymorphic, showing three single nucleotide polymorphisms (C>G at +16, -341, -408) and a deletion of two base pairs at -66 (AG>-) that is located close to the CCAAT box (-70) and the GC box (-86). Transcriptional activity associated with MICB promoter variants carrying this deletion, present in the 45.3% of Spanish population, showed a remarkable decrease (18-fold, p <0.01). By functional analysis, we show that the deletion plays a critical role in MICB promoter activity by diminishing Sp1 transcriptional activation. These important variations in MICB expression among normal individuals could imply a significant difference in the natural immune response against infections or tumor transformation, and might thereby contribute to an increased aberrant immune response against self cells, providing the molecular basis for the associations of the MICB gene to different autoimmune diseases.

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Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients

Cited by 134 publications

References 27 publications

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

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