ADAM15 is involved in MICB shedding and mediates the effects of gemcitabine on MICB shedding in PANC-1 pancreatic cancer cells

Abstract

The aim of this study was to investigate the role of ADAM15 in MHC class I polypeptide-related sequence B (MICB) protein ectodomain shedding and observe whether or not gemcitabine affects MICB shedding from PANC-1 cells. In this study, immunohistochemistry of MICB and ADAM15 were performed on tumor samples obtained from 93 patients with pancreatic ductal adenocarcinoma (PDAC). The expression of MICB and ADAM15 in the PDAC tissues was significantly higher compared with that in the normal tissues of the pancreas. Statistical analysis showed a significant correlation between the expression of MICB and certain classic clinicopathological characteristics (i.e., histological grade and TNM stage). ADAM15 expression was found to correlate with lymph node metastasis and TNM stage. The Spearman's rank test suggested that the expression of MICB was inversely correlated with that of ADAM15 in PDAC tissues. Knockdown of ADAM15 in PANC-1 cells clearly upregulated MICB expression on the cellular surface and downregulated soluble MICB (sMICB) levels in the culture supernatants. A non-toxic dose of 0.5 µmol/l gemcitabine suppresses ADAM15 expression leading, at the same time, to an increase in MICB expression and a decrease in sMICB production in PANC-1 cells. The mRNA levels of MICB did not change following PANC-1 exposure to gemcitabine. Further study suggests that the suppressive effect of gemcitabine on MICB shedding in PANC-1 cells is mediated by ADAM15 downregulation. In conclusion, the results of the present study support the hypothesis that ADAM15 is involved in MICB shedding of PANC-1 cells and that gemcitabine inhibits MICB ectodomain shedding through the suppression of ADAM15.

Soluble MICA is elevated in pancreatic cancer: Results from a population based case‐control study

“…To date, several epidemiological studies have demonstrated elevated s‐MICA levels in multiple cancers, and its association with pancreatic cancer risk . We sought to confirm these findings using a more robust design through a population‐based case control study, after adjusting for demographic and lifestyle characteristic of the study participants.…”

“…The shedding of MICA inhibits NK cells in the tumor microenvironment, enabling tumor cells to avoid lysis by NK cells . Consistent with this mechanism, increased blood levels of s‐MICA have been correlated with advanced cancer stage at diagnosis, metastasis, and worse prognosis in liver,colorectal, oral cancers, leukemia, and pancreatic cancer . In addition, s‐MICA has been studied as a potential biomarker to monitor the status and treatment of malignant disease in liver and pancreatic carcinomas …”

“…Several epidemiologic studies have reported positive associations between s‐MICA levels and pancreatic cancer . Specifically, previous case‐control studies found that pancreatic cancer was associated with significant increases in s‐MICA.…”

“…The shedding of MICA into the blood leads to the surface depletion of MICA and down regulation of NKG2D receptor on NK cells . By binding to the NKG2D receptor, MICA can block the activation of NK cells, thereby decreasing the ability of NK cells to recognize and mount a response to kill tumor cells.…”

Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

“…MMP9 has been observed to proteolytically cleave both MICA and MICB in osteosarcoma cells (U-2 OS and SaOS-2) 59 . Furthermore, it has recently been reported that ADAM metallopeptidase 15 (ADAM15) and MICB are strongly expressed in PDAC and their expression correlates with tumor stage 60 . Thus, when ADAM15 activity is blocked in PANC-1 cells, the release of sMICB is suppressed, enhancing MICB expression on the cell surface.…”