Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness

Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes

Association of Human Leukocyte Antigen with Interstitial Lung Disease in Rheumatoid Arthritis: A Protective Role for Shared Epitope

INTRODUCTION: Interstitial Lung Disease (ILD) is frequently associated with Rheumatoid Arthritis (RA) as one of extra-articular manifestations. Many studies for Human Leukocyte Antigen (HLA) allelic association with RA have been reported, but few have been validated in an RA subpopulation with ILD. In this study, we investigated the association of HLA class II alleles with ILD in RA. METHODS: An association study was conducted on HLA-DRB1, DQB1, and DPB1 in 450 Japanese RA patients that were or were not diagnosed with ILD, based on the findings of computed tomography images of the chest. RESULTS: Unexpectedly, HLA-DRB1*04 (corrected P [Pc] = 0.0054, odds ratio [OR] 0.57), shared epitope (SE) (P = 0.0055, OR 0.66) and DQB1*04 (Pc = 0.0036, OR 0.57) were associated with significantly decreased risk of ILD. In contrast, DRB1*16 (Pc = 0.0372, OR 15.21), DR2 serological group (DRB1*15 and *16 alleles) (P = 0.0020, OR 1.75) and DQB1*06 (Pc = 0.0333, OR 1.57, respectively) were significantly associated with risk of ILD. CONCLUSION: HLA-DRB1 SE was associated with reduced, while DR2 serological group (DRB1*15 and *16) with increased, risk for ILD in Japanese patients with RA

HLA class II allele frequency in the RA patients.

<p>ILD(+)RA: ILD positive RA, ILD(−)RA: ILD negative RA, OR: odds ratio, 95%CI: confidence interval, <i>Pc</i>: corrected <i>P</i> value, NS: not significant. Allele frequencies are shown in parenthesis (%). Association was tested by Fisher’s exact test using 2×2 contingency tables.</p

HLA-DRB1 allele frequency in the RA patients.

<p>ILD(+)RA: ILD positive RA, ILD(−)RA: ILD negative RA, OR: odds ratio, 95%CI: confidence interval, <i>Pc</i>: corrected <i>P</i> value, NS: not significant. Allele frequencies are shown in parenthesis (%). Association was tested by Fisher’s exact test using 2×2 contingency tables.</p

SE and DR2 frequency in the all RA patients and RA patients without SE or DR2.

<p>ILD(+)RA: ILD positive RA, ILD(−)RA: ILD negative RA, OR: odds ratio, 95%CI: confidence interval, SE: Shared epitope. Genotype or allele frequencies are shown in parenthesis (%). Association was tested by chi-square analysis or Fisher’s exact test using 2×2 contingency tables under the indicated models for SE or DR2. *Fisher’s exact test was employed.</p

HLA-DRB1 allele frequency in the RA patients and controls.

<p>ILD(+)RA: ILD positive RA, ILD(−)RA: ILD negative RA, OR: odds ratio, 95%CI: confidence interval, <i>Pc</i>: corrected <i>P</i> value, NS: not significant. Allele frequencies are shown in parenthesis (%). Association was tested by Fisher’s exact test using 2×2 contingency tables.</p

<i>HLA-DRB1</i> or <i>DQB1</i> allele carrier frequency in the RA cases with specific <i>DQB1</i> or <i>DRB1</i> alleles (two locus analysis).

<p>ILD(+)RA: ILD positive RA, ILD(−)RA: ILD negative RA, OR: odds ratio, 95%CI: confidence interval, <i>Pc</i>: corrected <i>P</i> value, NS: not significant. Allele frequencies are shown in parenthesis (%). Association was tested by Fisher’s exact test using 2×2 contingency tables.</p

Characteristics of RA patients.

<p>ILD(+)RA: ILD positive RA, ILD(−)RA: ILD negative RA. Association was tested by chi-square analysis using 2×2 contingency tables or Student’s t-test.</p>*<p>Student’s t-test was employed.</p