| Abstract | Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, this disease is most likely to be discovered when already having progressed to an advanced stage that is palliatively treated with conventional or cytotoxic chemotherapeutics. The latter typically involves 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11), first-line therapeutics that stumble upon chemoresistance in the majority of cases of metastatic or advanced CRC.
This study aims to integrate the results derived from different studies in CRC cancer, found on PubMed, and finally to bioinformatically process them in order to identify some novel molecular features of drug resistance that could be specifically targeted in order to sensitize CRC to conventional chemotherapy. The first step was to analyse the complex interactions between biomarkes of chemoresistance to 5-FU, Ox and CPT-11 with the help of STRING. The STRING-derived PPI network was then imported in cytoHubba to yield hub genes based on their number of interactions. Enrichments in DAVID biological processes, cell compartments and molecular functions as well as enrichments in KEGG pathways were also investigated.
As a result, newly identified hub genes were yielded for the chemoresistance to 5-FU (RPL8, RPS18, RPS11), Ox (ERCC3, ERCC4) and CPT-11 (CTNNB1, CTNND1). Also, pathways in common to the resistance to all three drugs were determined: miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. Targeting the hub genes and signalling pathways proposed in this review might be effective against chemoresistance to conventional chemotherapy. |
| Abstract (croatian) | Karcinom debelog crijeva učestala je zloćudna bolest koja pogađa oba spola. Najčešće se otkrije tek u trećoj ili četvrtoj fazi, a tada se palijativno tretira citotoksičnim kemoterapeuticima-5-fluorouracilom (5-FU), oksaliplatinom (Ox), irinotekanom (CPT-11). Učinak navedenih lijekova smanjuje se radi razvoja kemorezistencije, koja je ujedno i najčešći ishod dugotrajnijeg tretiranja napredne i metastatske faze karcinoma debelog crijeva.
Svrha ovog revijalnog rada bila je sažimanje rezultata znanstvenih radova s naglaskom na mehanizme kemorezistencije u kolorektalnom karcinomu. Znanstveni radovi pretraženi su putem online baze podataka PubMed, a izdvojeni biomarkeri kemorezistencije zatim su bioinformatički analizirani. Bioinformatičkom analizom identificirale su se nove molekularne značajke kemorezistencije na koje bi se moglo farmakološki djelovati u svrhu pojačavanja odgovora kolorektalnog carcinoma na 5-FU, Ox i CPT-11.
Platformom STRING dobivene su proteinske interakcijske mreže, iz kojih su programom cytoHubba izdvojeni hub geni ključni za kemorezistenciju na 5-FU, Ox te CPT-11. Zatim, programima DAVID i KEGG odredili su se biološki procesi, dijelovi stanice, molekulske funkcije te signalizacijski putevi u kojima sudjeluju istraženi biomarkeri .
Na kraju, novoidentificirani su hub geni koji bi mogli igrati ulogu u kemorezistenciji na 5-FU (RPL8, RPS18, RPS11), Ox (ERCC3, ERCC4) i CPT-11 (CTNNB1, CTNND1 te signalizacijski putevi zastupljeni u kemorezistenciji na sva tri lijeka: miRNA i proteoglikani u raku, stanična senescencija te signalni put sfingolipida. Ciljanje novoidentificiranih hub gena i signalizacijskih puteva, moglo bi se pokazati uspješnim protiv kemorezistencije na konvencionalnu kemoterapiju.
Ključne riječi: karcinom debelog crijeva, 5-fluorouracil, oxaliplatin, irinotecan, kemorezistencija |
