A Dual Role for KRT81: A miR-SNP Associated with Recurrence in Non-Small-Cell Lung Cancer and a Novel Marker of Squamous Cell Lung Carcinoma

Abstract

MicroRNAs (miRNAs) play an important role in carcinogenesis through the regulation of their target genes. miRNA-related single nucleotide polymorphisms (miR-SNPs) can affect miRNA biogenesis and target sites and can alter microRNA expression and functions. We examined 11 miR-SNPs, including 5 in microRNA genes, 3 in microRNA binding sites and 3 in microRNA-processing machinery components, and evaluated time to recurrence (TTR) according to miR-SNP genotypes in 175 surgically resected non-small-cell lung cancer (NSCLC) patients. Significant differences in TTR were found according to KRT81 rs3660 (median TTR: 20.3 months for the CC genotype versus 86.8 months for the CG or GG genotype; P = 0.003) and XPO5 rs11077 (median TTR: 24.7 months for the AA genotype versus 73.1 months for the AC or CC genotypes; P = 0.029). Moreover, when patients were divided according to stage, these differences were maintained for stage I patients (P = 0.002 for KRT81 rs3660; P<0.001 for XPO5 rs11077). When patients were divided into sub-groups according to histology, the effect of the KRT81 rs3660 genotype on TTR was significant in patients with squamous cell carcinoma (P = 0.004) but not in those with adenocarcinoma. In the multivariate analyses, the KRT81 rs3660 CC genotype (OR = 1.8; P = 0.023) and the XPO5 rs11077 AA genotype (OR = 1.77; P = 0.026) emerged as independent variables influencing TTR. Immunohistochemical analyses in 80 lung specimens showed that 95% of squamous cell carcinomas were positive for KRT81, compared to only 19% of adenocarcinomas (P<0.0001). In conclusion, miR-SNPs are a novel class of SNPs that can add useful prognostic information on the clinical outcome of resected NSCLC patients and may be a potential key tool for selecting high-risk stage I patients. Moreover, KRT81 has emerged as a promising immunohistochemical marker for the identification of squamous cell lung carcinoma.

A microRNA-related single nucleotide polymorphism of the XPO5 gene is associated with survival of small cell lung cancer patients

“…The altered expression of a number of miRNAs has been found to predict anticancer treatments (22). In previous reports (19), rs11077 has been identified to be associated with recurrence in post-operative NSCLC patients. In the present study, we report that the miR-SNP in miRNA processing machinery genes of XPO5 are involved in the prognosis of SCLC outcome.…”

“…A miR-SNP of rs11077 located in the 3'UTR of the miRNA processing gene XPO5 has shown its association with the chemotherapeutic response in metastatic colon cancer as well as recurrence in resected non-small cell lung cancer (NSCLC) (9,19). In the present study, we evaluated the predictive power of this SNP on the overall survival of SCLC patients.…”

“…Additionally, the RNA-induced silencing complex (RISC) including GEMIN3 and GEMIN4 selects a single strand as the mature miRNA and guides the mature miRNAs to their target mRNA sites (10,(13)(14)(15)(16). miRNA-related single nucleotide polymorphisms (miR-SNPs), defined as SNPs in miRNA genes, miRNA binding site and miRNA processing machinery, are able to modulate miRNA and target gene expressions in order to influence cancer risk, treatment efficacy and patient prognosis (9,(17)(18)(19)(20).…”

“…Additionally, the RNA-induced silencing complex (RISC) including GEMIN3 and GEMIN4 selects a single strand as the mature miRNA and guides the mature miRNAs to their target mRNA sites (10,13-16). miRNA-related single nucleotide polymorphisms (miR-SNPs), defined as SNPs in miRNA genes, miRNA binding site and miRNA processing machinery, are able to modulate miRNA and target gene expressions in order to influence cancer risk, treatment efficacy and patient prognosis (9,(17)(18)(19)(20).A miR-SNP of rs11077 located in the 3'UTR of the miRNA processing gene XPO5 has shown its association with the chemotherapeutic response in metastatic colon cancer as well as recurrence in resected non-small cell lung cancer (NSCLC) (9,19). In the present study, we evaluated the predictive power of this SNP on the overall survival of SCLC patients.…”

MicroRNA polymorphisms as markers of risk, prognosis and treatment response in hematological malignancies

“…In multiple myeloma, both homoand heterozygous carriers of the variant C allele of rs11077 also had longer overall and progression-free survival (PFS) [30]. This polymorphism was also studied in lung cancer and while in non-small cell lung cancer the C allele was associated with better prognosis and treatment response [31,32], similarly to Hodgkin lymphoma and multiple myeloma, in small cell lung cancer it was the A allele that conferred longer survival but the study group was rather small [33]. rs11077 is located in the 3 UTR of XPO5 and it could influence miRNA binding to the transcript.…”