Novel molecular biomarkers of cancer therapy-induced cardiotoxicity in adult population: a scoping review.

AIM: Cancer treatments are associated with cardiotoxic events that predispose to cardiac pathology and compromise the survival of patients, making necessary the identification of new molecular biomarkers to detect cardiotoxicity. This scoping review aims to identify the available evidence on novel molecular biomarkers associated with cardiotoxicity in the adult population undergoing cancer therapy. METHODS AND RESULTS: The databases Medline, Web of Science, Scopus, and Embase were screened for the identification of published studies until 23 August 2020, searching for novel molecular biomarkers reported in cancer therapy-related cardiac dysfunction in adult patients. A total of 42 studies that met the eligibility criteria were included. Fourteen studies reported 44 new protein biomarkers, 18 studies reported 57 new single nucleotide polymorphism biomarkers, and 11 studies reported 171 new gene expression profiles associated with cardiotoxicity. Data were extracted for 272 novel molecular biomarkers reported and evaluated in 7084 cancer patients, of which only 13 were identified in more than one study (MPO, sST2, GDF-15, TGF-B1, rs1056892, rs1883112, rs4673, rs13058338, rs1695, miR-1, miR-25-3p, miR-34a-5p, and miR-423-5p), showing values for area under the curve > 0.73 (range 0.74-0.85), odds ratio 0.26-7.17, and hazard ratio 1.28-1.80. CONCLUSIONS: Multiple studies presented a significant number of novel molecular biomarkers as promising predictors for risk assessment of cardiac dysfunction related to cancer therapy, but the characteristics of the studies carried out and the determinations applied do not allow suggesting the clinical use of these molecular biomarkers in the assessment of cancer therapy-induced cardiotoxicity.

Correction: New localization and function of calpain-2 in nucleoli of colorectal cancer cells in ribosomal biogenesis: effect of KRAS status.

[This corrects the article DOI: 10.18632/oncotarget.23888.].

New localization and function of calpain-2 in nucleoli of colorectal cancer cells in ribosomal biogenesis: effect of KRAS status.

Calpain-2 belongs to a family of pleiotropic Cys-proteases with modulatory rather than degradative functions. Calpain (CAPN) overexpression has been controversially correlated with poor prognosis in several cancer types, including colorectal carcinoma (CRC). However, the mechanisms of substrate-recognition, calpain-2 regulation/deregulation and specific functions in CRC remain elusive. Herein, calpain subcellular distribution was studied as a key event for substrate-recognition and consequently, for calpain-mediated function. We describe a new localization for calpain-2 in the nucleoli of CRC cells. Calpain-2 nucleolar distribution resulted dependent on its enzymatic activity and on the mutational status of KRAS. In KRASWT/- cells serum-starvation induced CAPN2 expression, nucleolar accumulation and increased binding to the rDNA-core promoter and intergenic spacer (IGS), concomitant with a reduction in pre-rRNA levels. Depletion of calpain-2 by specific siRNA prevented pre-rRNA down-regulation after serum removal. Conversely, ribosomal biogenesis proceeded in the absence of serum in unresponsive KRASG13D/- cells whose CAPN2 expression, nucleolar localization and rDNA-occupancy remained unchanged during the time-course of serum starvation. We propose here that nucleolar calpain-2 might be a KRAS-dependent sensor to repress ribosomal biogenesis in growth limiting conditions. Under constitutive activation of the pathway commonly found in CRC, calpain-2 is deregulated and tumor cells become insensitive to the extracellular microenvironment.

EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells.

KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was also dependent on KRAS mutational status. Several hnRNP family members were identified within the 36 acetylated-proteins. Acetylation status is known to be involved in the modulation of EGF-response. In agreement with results presented herein, hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells, whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells. Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status. Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge.