ABSTRACT
Neuroblastoma poses significant challenges in clinical management. Despite its relatively low incidence, this malignancy contributes disproportionately to cancer-related childhood mortality. Tailoring treatments based on risk stratification, including MYCN oncogene amplification, remains crucial, yet high-risk cases often confront therapeutic resistance and relapse. Here, we explore the aryl hydrocarbon receptor (AHR), a versatile transcription factor implicated in diverse physiological functions such as xenobiotic response, immune modulation, and cell growth. Despite its varying roles in malignancies, AHR's involvement in neuroblastoma remains elusive. Our study investigates the interplay between AHR and its ligand kynurenine (Kyn) in neuroblastoma cells. Kyn is generated from tryptophan (Trp) by the activity of the enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). We found that neuroblastoma cells displayed sensitivity to the TDO2 inhibitor 680C91, exposing potential vulnerabilities. Furthermore, combining TDO2 inhibition with retinoic acid or irinotecan (two chemotherapeutic agents used to treat neuroblastoma patients) revealed synergistic effects in select cell lines. Importantly, clinical correlation analysis using patient data established a link between elevated expression of Kyn-AHR pathway genes and adverse prognosis, particularly in older children. These findings underscore the significance of the Kyn-AHR pathway in neuroblastoma progression, emphasizing its potential role as a therapeutic target.
Subject(s)
Kynurenine , Neuroblastoma , Receptors, Aryl Hydrocarbon , Humans , Kynurenine/metabolism , Neuroblastoma/pathology , Neuroblastoma/metabolism , Neuroblastoma/genetics , Neuroblastoma/drug therapy , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Cell Line, Tumor , Tryptophan Oxygenase/metabolism , Tryptophan Oxygenase/genetics , Tryptophan Oxygenase/antagonists & inhibitors , Tretinoin/pharmacology , Signal Transduction/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
