<p>Differential gene expression identifies KRT7 and MUC1 as potential metastasis-specific targets in sarcoma</p>

Abstract

BackgroundDespite numerous discoveries regarding the molecular genesis and progression of primary cancers, the biology of metastasis remains poorly understood. Compared to very large numbers of circulating tumor cells that are now known to accompany nearly all cancers, a relatively limited number of lesions actually develop in most patients with metastases. We hypothesized that phenotypic changes driven by differential gene expression in a finite subpopulation of tumor cells render those cells capable of metastasis and sought to identify key pathways through analysis of gene expression in primary and metastatic lesions from the same patients.MethodsWe compared whole-genome expression in 4 matched samples of primary and metastatic sarcoma, then evaluated candidate genes with differential expression via quantitative PCR in 30 additional matched sets, tumor tissue immunostaining, siRNA loss-of-function in a sarcoma cell migration assay, and clinical correlation with overall and disease-free survival after metastasectomy.ResultsComparison of microarray signals identified differential expression of cell adhesion genes, including upregulation of KRT7 and MUC1 in metastases; KRT7 and MUC1 upregulation was confirmed in 22 (73%) and 20 (67%) matched sets of metastatic/primary tumors, respectively. Silencing of KRT7 and MUC1 via targeted siRNAs suppressed sarcoma cell migration in vitro, and a significant correlation (two-sided) was observed between both KRT7 and MUC1 expression in metastases and overall patient survival.ConclusionKRT7 and MUC1 may play a significant role in enabling sarcoma metastasis, and they may therefore be important prognostic biomarkers as well as potential targets for therapeutic prevention of metastasis.

12 Survival-related differentially expressed genes based on the TARGET-osteosarcoma database

“…41 Interestingly, high expression level of MUC1 in sarcoma metastasis was correlated with worse overall survival in sarcoma. 26 Our result also correlated a high expression of MUC1 with low survival of OS patients (Figure 4(a)).…”

“…The associations between differentially regulated (both upregulated and downregulated) genes and OS have already been analyzed (except RAB40C, USP11 , CTNNBIP1, TNC2, GCA, JAG2 , and KAZALD1 ). 21–26 However, in these studies, the prognostic values of the genes have not been investigated.…”

MicroRNA‐216a targets WT1 expression and regulates KRT7 transcription to mediate the progression of pancreatic cancer—A transcriptome analysis

“…17 Although the direct links between KRT7 and the PC cell behaviors have been rarely studied, KRT7 has been widely reported to enhance growth and development of several cancers upon activation. 16,[34][35][36] In the present study, the subsequent rescue experiments suggested that overexpression of WT1 blocked the anti-tumor functions of miR-216a in PC cells; while silencing of KRT7 suppressed the oncogenic effects of WT1. In addition, either miR-216a upregulation or KRT7 silencing was found to suppress the phosphorylation of PI3K and AKT in PC cells, while WT1, as expected, activated the PI3K/ AKT signaling pathway, indicating that miR-216a mediates the WT1/KRT7 axis and impairs the PI3K/AKT pathway to suppress PC progression.…”

“…Likewise, stable high expression of KRT7 has been found in the clinical PC samples compared to the pseudotumoural chronic pancreatitis 17 . Although the direct links between KRT7 and the PC cell behaviors have been rarely studied, KRT7 has been widely reported to enhance growth and development of several cancers upon activation 16,34–36 . In the present study, the subsequent rescue experiments suggested that overexpression of WT1 blocked the anti‐tumor functions of miR‐216a in PC cells; while silencing of KRT7 suppressed the oncogenic effects of WT1.…”

Identification of Methylation Driven Biomarkers for Diagnosis and Prognosis in Colon Cancer by Integrative Analysis of TCGA, GTEx, and GEO Data

“…Previous studies showed that KRT7 play a signi cant role in tumor metastasis and considered as prognostic biomarker and potential targets for therapeutic prevention of metastasis. [16] In addition, KRT7 was down-regulated and hypermethylated in CRC tissues compared with adjacent normal tissues and may lead to the occurrence of CRC. [26] 7) STK33 (Serine/threonine kinase 33) was experimentally demonstrated that downregulation and hypermethylation of STK33 in CRC tissues compared with normal tissues with P < 0.001, and STK33 methylation was also remarkably associated with lymph node metastasis, tumor invasion, distant metastases and tumor stage.…”