Abstract
Impairment of the immune response and aberrant expression of microRNAs are emerging hallmarks of tumour initiation/progression, in addition to driver gene mutations and epigenetic modifications. We performed a preliminary survey of independent adenoma and colorectal cancer (CRC) miRnoma data sets and, among the most dysregulated miRNAs, we selected miR-27a and disclosed that it is already upregulated in adenoma and further increases during the evolution to adenocarcinoma. To identify novel genes and pathways regulated by this miRNA, we employed a differential 2DE-DIGE proteome analysis. We showed that miR-27a modulates a group of proteins involved in MHC class I cell surface exposure and, mechanistically, demonstrated that calreticulin is a miR-27a direct target responsible for most downstream effects in epistasis experiments. In vitro miR-27a affected cell proliferation and angiogenesis; mouse xenografts of human CRC cell lines expressing different miR-27a levels confirmed the protein variations and recapitulated the cell growth and apoptosis effects. In vivo miR-27a inversely correlated with MHC class I molecules and calreticulin expression, CD8+ T cells infiltration and cytotoxic activity (LAMP-1 exposure and perforin release). Tumours with high miR-27a, low calreticulin and CD8+ T cells' infiltration were associated with distant metastasis and poor prognosis. Our data demonstrate that miR-27a acts as an oncomiRNA, represses MHC class I expression through calreticulin downregulation and affects tumour progression. These results may pave the way for better diagnosis, patient stratification and novel therapeutic approaches.
Highlights
Antigens, these latter molecules dissociate from the peptide-loading complex (PLC) and translocate to the cell surface where they are recognized by cells of the immune system, contributing to immune surveillance.[9,10,11]
We selected miR-27a for further analysis and assessed its expression in our series of adenomas (n = 32) and sporadic Colorectal cancer (CRC) (n = 80) by quantitative RT-PCR analysis. miR-27a was already elevated in about 60% of adenomas and further increased during tumour progression, suggesting that its aberrant expression is an early event in colon tumourigenesis (Figure 1D)
By a 2DE-DIGE proteomic approach, we identify a series of proteins modulated by miR-27a implicated in major histocompatibility complex (MHC) class I expression
Summary
Antigens, these latter molecules dissociate from the PLC and translocate to the cell surface where they are recognized by cells of the immune system, contributing to immune surveillance.[9,10,11]. Defects of MHC class I antigen presentation occur at high frequency in solid tumours and is a feature of tumour immune evasion that renders cancer cells invisible to cytotoxic T cell. A selective loss or reduced level of MHC class I is generally associated with disease progression and reduced patient survival. Received 01.12.15; revised 22.12.15; accepted 05.1.16; Edited by G Melino miR-27a represses MHC class I surface exposure T Colangelo et al under intense investigation. Using a proteomic approach, we identified a series of new proteins modulated by miR-27a that are involved in MHC class I cell surface exposure. MiR-27a is overexpressed in a large proportion of human sporadic CRCs, inversely correlates with MHC class I molecules and calreticulin and CD8+ T cells' infiltration and activity. The combination of high miR-27a/low calreticulin is associated with distant metastasis and worse outcome
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