P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3′-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.

MicroRNA 320, an Anti-Oncogene Target miRNA for Cancer Therapy

“…According to other recent studies supporting the notion that miR-320 functions as a tumor repressor, other evidence is needed for demonstrating that miR-320 plays a carcinogenic role. Several studies have shown that miR-320 is upregulated in tumors and promotes proliferation, migration, invasion, and reduced cancer cell sensitivity to chemotherapeutics [ 54 , 57 , 58 ], suggesting that miR-320 pro-tumoral or anti-tumoral functions are context-dependent. Combined with the above studies from various cancers listed in Table 1 , many figures have indicated that the miR-320 family plays a vital role not only in repressing EMT, but also in tumor cell metastases and invasion.…”

“…Transcriptional regulation and epigenetic modification are two significant mechanisms that control miRNA expression [ 57 , 64 , 100 , 101 ]. As the miR-320 family acts as a tumor repressor has attracted increasing interest in many human tumors, and transforming the tumor suppression signal from miR-320 may be a new strategy to treat cancers in the future.…”

“…E2A was found to directly bind to miR-320a’s E-box, thereby upregulating its expression [ 101 ]. Costa et al [ 57 ] found that the inhibitory function of p53 on tumor escape was involved the transactivation of hsa-miR-320a-3p. hsa-miR-320a-3p repression of PDL1 was associated with p53 regulated tumor escape [ 57 ].…”

“…Costa et al [ 57 ] found that the inhibitory function of p53 on tumor escape was involved the transactivation of hsa-miR-320a-3p. hsa-miR-320a-3p repression of PDL1 was associated with p53 regulated tumor escape [ 57 ]. In addition, Δ Np63α is a member of the p53 TF family, which regulates the transcription of miR-320 by binding to the p63 binding site 6 kb downstream of hsa-miR-320a-3p [ 37 ].…”

How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers

“…al., identified lower expression of miR-320 in mesothelioma tumors compared to normal tissues by performing differential miRNA expression analysis on 14 formalin-fixed paraffinembedded tumors and six normal controls (60). They also identified an association between p53-induced expression of miR-320, miR-200a and miR-34a with reduced expression of PD-L1 in mesothelioma cell lines (60). These data indicate defective p53-induced miRNA response as a possible contributor to immune evasion in mesothelioma by increasing tumor PD-L1 expression (60).…”