miRNA regulation is important for DNA damage repair and recognition in malignant pleural mesothelioma

Abstract

Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString). We defined a small subset of miRNAs regulating the key enzymes involved in the repair of platin-associated DNA damage. Particularly, the TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main miRNA targets within this context. The TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main players for risk stratification in patients suffering from this severe disease. Taking the specific molecular profile of the tumour into account can help to enhance the clinical management prospectively and to smooth the way to better response prediction.

Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy

“…Secondly, MTs might act as a negative regulator of the effect of the chemotherapy by sequestering zinc ions [ 60 , 61 ], thereby regulating proteins based on zinc ions as cofactor like p53. We also compared MT expression presented within this study with results on p53 and mdm2 from previous investigation from our group [ 16 , 18 , 62 – 64 ]. However, we could not define significant associations between the two pathways.…”

“…Notwithstanding this, p53 is an essential regulator for apoptosis in case of DNA damage repair and recognition [ 60 ] and plays an important role in tumorigenesis and response to alkylating chemotherapeutics [ 16 , 18 , 62 – 64 ]. Previously, possible correlations to clinic-pathological data with the tumor suppressors p53 and MTs were analyzed in MPM samples but revealed no statistical association as well as no correlation to each other [ 39 ].…”

“…It is however uncertain whether the failure of this mechanism alone is responsible for the impaired therapy response. Several studies have therefore attempted to identify molecular properties shared by MPMs to understand the basis of the poor treatment response [ 8 , 11 , 14 – 18 ].…”

Biomarkers for Early Diagnosis and Prognosis of Malignant Pleural Mesothelioma: The Quest Goes on

“…In recent years, the use of miRNAs has been proposed as biomarkers for various neoplastic pathologies, including pleural MM [ 91 , 92 ]. Several research groups analysed and compared circulating miRNAs in serum samples from patients with MM, workers exposed to asbestos and healthy subjects [ 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ].…”

“…Currently, literature proposes the stratification of high-risk subjects and an early diagnosis of MM through the perusal of the following pool of blood analysis: miRNA-126-3p, miRNA-625-3p and miRNA-103a-3p in pairing with mesothelin and fibulin-3. Instead, for MM patients, the analysis of miRNA-16-5p, miRNA-126-3p, miRNA-143-3p, miRNA-145-5p, miRNA-192-5p, miRNA-193a-3p, miRNA-200b-3p, miRNA-203a-3p and miRNA-652-3p might be useful to monitor sensitivity to therapy and for prognostic purposes [ 92 , 94 , 95 , 96 , 97 ]. The scientific community, however, constantly updates the miRNA which can be associated with MM early diagnosis and prognosis.…”