MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma

Javle

et al. 2016

Cancer

Background BTC are uncommon and associated with a dismal prognosis. Gemcitabine and platinum-combinations (GP) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for GP response in BTC, we evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Methods Pretreatment FFPE samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression free survival (PFS) and overall survival (OS). Results Considering genes with an incidence >10%, no individual gene was independently predictive of GP response. In patients with unresectable BTC who received GP as first-line therapy, the joint status of CDKN2A, TP53 and ARID1A were associated with PFS (P=0.0004) and OS (P=<0.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor prognostic cohort with a median PFS and OS of 2.63 and 5.22 months. Patients with mutant ARID1A regardless of single mutational status of TP53 or CDKN2A had similar outcomes. A patient who exhibited mutations in all three genes had a median PFS of 20.37 months and OS not reached. Conclusions In the largest exploratory analysis of this nature in BTC, the presence of three prevalent, mutually exclusive mutations represents distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker to GP response. Prospective studies validate these findings are needed, including the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC.

Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance

Javle

et al. 2016

Cancer

“…Both miR-99a and miR-491 may play different roles in various cancers as they regulated different target genes. The miR-99a has been reported to regulate resistance in breast cancer 18, leukemia 19, neck squamous cell carcinoma 20, germ cell tumor 21, pancreatic ductal adenocarcinoma 22, cholangiocarcinoma23, etc. The relation between miR-491 and liver cancer 24, colorectal cancer 25, ovarian carcinoma 26, pancreatic cancer 27, oral squamous cell carcinoma 28, non-small cell lung cancer 29, etc has also been verified.…”

Section: Discussionmentioning

confidence: 99%

MiR-99a and MiR-491 Regulate Cisplatin Resistance in Human Gastric Cancer Cells by Targeting CAPNS1

Zhang¹,

Xu²,

Ni³

et al. 2016

Int. J. Biol. Sci.

Cisplatin is the first-line agent utilized for the clinical treatment of a wide variety of solid tumors including gastric cancer. However, the intrinsic or acquired cisplatin resistance is often occurred in patients with gastric cancer and resulted in failure of cisplatin therapy. In order to investigate if miRNA involves in cisplatin resistance of human gastric cancer, we first screened and compared the expression of miRNAs between cisplatin resistant gastric cancer cell lines SGC-7901/DDP and BGC-823/DDP and their sensitive parental cells by miRNAs microarray and followed by analysis of 2D-GE/MS to identify their target proteins. We found both miR-99a and miR-491 were upregulated while their target gene calpain small subunit 1 (CAPNS1) was downregulated in resistant gastric cancer cells. Dual-luciferase- reporter assays with wild-type and mutated CAPNS1 3'-UTR confirmed their specificity of targeting. Inhibition of miR-99a and miR-491, or overexpress CAPNS1 can enhance cisplatin sensitivity of the resistant cells while transfection of two miRNAs' mimics or si-CAPNS1 in the sensitive cells can induce their resistance. Moreover, our results demonstrated CAPNS1 positively regulated calpain1 and calpain2, the catalytic subunits of CAPNS1, and cleaved caspase3 which further cleaved PARP1 and directly induced apoptosis. Therefore, miR-99a and miR-491 might be work as novel molecules regulate cisplatin resistance by directly targeting CAPNS1 associated pathway in human gastric cancer cells.

“…In essence, over 10% of all reported research findings of miRNA influences in cancer chemoresistance demonstrated that such a phenotype modulation was effected through simultaneous dysregulation of multiple miRNAs, rather than an individual putative chemoresistance miRNA—though no specific miRNA combination was identified as most prevalent by the authors [44,46,47,48,49,62,67,71,76,81,85,88,132,133,158,168,201,203,211,212,213,217,223,224,228,230]. This suggests that miRNA influences on cellular functions also occur at a more complex level, whereby it is a signature dysregulated expression pattern of two (or more) miRNAs that trigger simultaneous downregulation of a specific set of target transcripts leading to an ultimate change in cellular/tissue phenotype.…”

Section: Influences Of Mirnas In Cancer Chemoresistancementioning

confidence: 99%

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

Ayers

Vandesompele

2017

Genes

101

Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology.