Study clarifies the role of KLF12 in tumor growth CRC -
The results of the preclinical studies by MUSC researchers reported in the July 2016 issue PLOS One , demonstrate for the first time that the KLF12 transcription factor promotes cell growth CRC, in part, by the activation EGR1. In addition, the data demonstrate that KLF12 levels correlate EGR1 in synergy with bad CRC prognosis.
CRC is the third most common cancer and the third most deadly in the United States. Like most cancers, CRC development is stimulated by a series of genetic changes and epigenetic changes that modify gene expression. In turn, this expression of the modified gene initiates tumor and supports their progress. Thus, transcription factors that regulate gene expression and signal transduction pathways during carcinogenesis have long been studied as potential therapeutic targets.
Dr. Raymond DuBois, dean of the MUSC College of Medicine, professor of biochemistry and molecular biology and senior author of the article focuses on understanding the role of inflammation in cancer. "We studied the links between inflammation and cancer in my lab for a while now and we have determined that certain inflammatory mediators stimulate the progression of cancer," said DuBois. "We found that KLF12 increased so spectacular in the presence of inflammation in some cancers, so we tried to determine the specific molecular mechanisms responsible for these effects. "
transcription factor
other researchers studying the development of previously identified as a kidney KLF12 repressor of gene transcription of the AP-2α. It was then discovered that the expression AP-2α is also reduced in the tissues of the extended CRC tumor compared to the matched normal tissue and the loss of AP 2α promoted CRC invasion. that connection illuminates a potential link between KLF12 and CRC. in vitro studies show that KLF12 promotes gastric cancer (GC) cell proliferation and invasion, and that the levels are elevated in about 40% of KLF12 poorly differentiated CG and are correlated with the tumor size. In addition, recent genome-wide analyzes found high levels of KLF12 in about 40% of adenocarcinomas of the esophagus and in 45% of salivary tumors. So far, however, the role of KLF12 CRC remained uncertain.
The MUSC research team has designed a series of in vitro and in vivo experiments to clarify the role of KLF12 in CRC. The first set of studies examined the expression of KLF12 in seven human cell lines CRC. They found that not only KLF12 was expressed in 6 cell lines 7, but also that its overexpression leads to number of cells increased and KLF12 knockdown leads to reduced cell numbers of. In addition, they also found that overexpression of KLF12 led to the formation of larger cecal tumor while KLF12 knockdown led to the formation of cecal smaller tumors compared to controls. Thus, this series of experiments indicates that the CRC KLF12 promotes growth by enhancing the proliferation of cancer cells and / or survival.
The next series of experiments focused on clarifying which KLF12 target genes may be involved in regulating the growth CRC. Using microarray tests, the researchers found that KLF12 overexpressing modified several genes EGR1. It was previously reported that KLF12 regulates the expression of certain target genes by binding to CACCC pattern. They found that the EGR1 promoter contains two binding motifs possible DNA KLF12 located -1488bp (pattern 1) and -808bp (ground 2) relative to the transcription initiation site. Using ChIP assay, the team of MUSC researchers found that KLF12 does indeed bind strongly to EGR1 2 promoter ground but not on the grounds 1. In vitro experiments have shown that both mRNA levels and protein, CRC cells with undetectable levels of KLF12 expressed very low levels of EGR1 compared to cells expressing high levels of KLF12. In vivo studies using mice implanted with tumor cells that overexpressed CRC KLF12 EGR1 showed that expression was upregulated compared to mice implanted with control cells. In addition, coloring CRC human tissue samples produced the same pattern. Taken together, these results indicate that active KLF12 directly EGR1 CRC.
The third set of experiments examined whether EGR1 mediated the effects of KLF12 on the growth of tumor cells. The results show that knockdown EGR1 the growth of tumor cells induced by reduced KLF12, while EGR1 overexpression promoted cell growth in vitro, CRC, and tumor growth in the mouse model. The results of this series of studies, thus, indicate that KLF12 improves cell growth by activating CRC EGR1.
The final set of experiments evaluated whether KLF12 and EGR1 levels correlate with prognosis of CRC patients. By using gene expression data from databases of publicly available DNA chips (Moffitt [n = 177] Vanderbilt Medical Center [n = 55]), the CRC patients were stratified by level of KLF12 and / or expression of EGR1. These data showed that patients with high levels of either KLF12 or EGR1 had poorer results compared to those with low levels of these genes, and those with high levels of KLF12 and EGR1 had rates the lowest survival.
This is the first study to clarify the role of KLF12 CRC in tumor growth and progression seems to happen, at least in part, by activating EGR1. The finding that the synergistic contributions of KLF12 and EGR1 produce the worst results in CRC patients illuminates their potential in the development of new therapies. Further studies are needed to further clarify the role of KLF12 in CRC progression and its potential as a new prognostic marker and therapeutic target.
CRC is the third most common cancer and the third most deadly in the United States. Like most cancers, CRC development is stimulated by a series of genetic changes and epigenetic changes that modify gene expression. In turn, this expression of the modified gene initiates tumor and supports their progress. Thus, transcription factors that regulate gene expression and signal transduction pathways during carcinogenesis have long been studied as potential therapeutic targets.
Dr. Raymond DuBois, dean of the MUSC College of Medicine, professor of biochemistry and molecular biology and senior author of the article focuses on understanding the role of inflammation in cancer. "We studied the links between inflammation and cancer in my lab for a while now and we have determined that certain inflammatory mediators stimulate the progression of cancer," said DuBois. "We found that KLF12 increased so spectacular in the presence of inflammation in some cancers, so we tried to determine the specific molecular mechanisms responsible for these effects. "
transcription factor
other researchers studying the development of previously identified as a kidney KLF12 repressor of gene transcription of the AP-2α. It was then discovered that the expression AP-2α is also reduced in the tissues of the extended CRC tumor compared to the matched normal tissue and the loss of AP 2α promoted CRC invasion. that connection illuminates a potential link between KLF12 and CRC. in vitro studies show that KLF12 promotes gastric cancer (GC) cell proliferation and invasion, and that the levels are elevated in about 40% of KLF12 poorly differentiated CG and are correlated with the tumor size. In addition, recent genome-wide analyzes found high levels of KLF12 in about 40% of adenocarcinomas of the esophagus and in 45% of salivary tumors. So far, however, the role of KLF12 CRC remained uncertain.
The MUSC research team has designed a series of in vitro and in vivo experiments to clarify the role of KLF12 in CRC. The first set of studies examined the expression of KLF12 in seven human cell lines CRC. They found that not only KLF12 was expressed in 6 cell lines 7, but also that its overexpression leads to number of cells increased and KLF12 knockdown leads to reduced cell numbers of. In addition, they also found that overexpression of KLF12 led to the formation of larger cecal tumor while KLF12 knockdown led to the formation of cecal smaller tumors compared to controls. Thus, this series of experiments indicates that the CRC KLF12 promotes growth by enhancing the proliferation of cancer cells and / or survival.
The next series of experiments focused on clarifying which KLF12 target genes may be involved in regulating the growth CRC. Using microarray tests, the researchers found that KLF12 overexpressing modified several genes EGR1. It was previously reported that KLF12 regulates the expression of certain target genes by binding to CACCC pattern. They found that the EGR1 promoter contains two binding motifs possible DNA KLF12 located -1488bp (pattern 1) and -808bp (ground 2) relative to the transcription initiation site. Using ChIP assay, the team of MUSC researchers found that KLF12 does indeed bind strongly to EGR1 2 promoter ground but not on the grounds 1. In vitro experiments have shown that both mRNA levels and protein, CRC cells with undetectable levels of KLF12 expressed very low levels of EGR1 compared to cells expressing high levels of KLF12. In vivo studies using mice implanted with tumor cells that overexpressed CRC KLF12 EGR1 showed that expression was upregulated compared to mice implanted with control cells. In addition, coloring CRC human tissue samples produced the same pattern. Taken together, these results indicate that active KLF12 directly EGR1 CRC.
The third set of experiments examined whether EGR1 mediated the effects of KLF12 on the growth of tumor cells. The results show that knockdown EGR1 the growth of tumor cells induced by reduced KLF12, while EGR1 overexpression promoted cell growth in vitro, CRC, and tumor growth in the mouse model. The results of this series of studies, thus, indicate that KLF12 improves cell growth by activating CRC EGR1.
The final set of experiments evaluated whether KLF12 and EGR1 levels correlate with prognosis of CRC patients. By using gene expression data from databases of publicly available DNA chips (Moffitt [n = 177] Vanderbilt Medical Center [n = 55]), the CRC patients were stratified by level of KLF12 and / or expression of EGR1. These data showed that patients with high levels of either KLF12 or EGR1 had poorer results compared to those with low levels of these genes, and those with high levels of KLF12 and EGR1 had rates the lowest survival.
This is the first study to clarify the role of KLF12 CRC in tumor growth and progression seems to happen, at least in part, by activating EGR1. The finding that the synergistic contributions of KLF12 and EGR1 produce the worst results in CRC patients illuminates their potential in the development of new therapies. Further studies are needed to further clarify the role of KLF12 in CRC progression and its potential as a new prognostic marker and therapeutic target.
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