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Metastatic Colorectal Cancer Linked to Transcription Factors, Gene Networks

NEW YORK (GenomeWeb) – A pair of investigators from China has identified four transcription factors — along with related long non-coding RNAs and target genes — that are suspected of contributing to colorectal cancer (CRC) metastases.

As they reported in Scientific Reports yesterday, the researchers used available RNA sequence, array-based genotype, DNA methylation, and mass spectrometry-based protein profile data to analyze samples from nearly 600 CRC patients with or without metastases.

Transcript and protein expression of four transcription factors — HNF4A, HSF1, MECP2, and RAD21 — appeared to shift in metastatic CRC, prompting subsequent bioinformatic, chromatin immunoprecipitation sequencing, and ATAC-seq analyses to narrow in on transcription factor targets and the lncRNAs interacting with them.

"In our study, we identified four transcription factors associated with colorectal cancer metastasis and implemented integrative analyses to profile their regulatory landscape from genomic levels to clinical phenotypes," Rui Guo, a researcher in the Department of Biochemistry and Molecular Biology at Shanxi Medical University and co-author Bin Zhou, a life science researcher at Tsinghua University, wrote.

While the genetic and environmental contributors to CRC tumors are complex, the duo noted that it has been especially difficult to narrow in on consistent contributors to dangerous, metastatic forms of the disease, prompting a search for transcription factors that spur on this process.

"In view of the [high] heterogeneity of colorectal cancer metastasis, it is urgent to identify molecular targets for clinical treatment," the authors explained.

To that end, the researchers considered patterns in liquid chromatography-mass spec-based proteomic data in 11 CRC patients with metastases and 79 without, from the Clinical Proteomics Tumor Analysis Consortium (CPTAC), along with RNA sequence data for 598 individuals with CRC who were assessed for the Cancer Genome Atlas (TCGA) project, including 88 individuals with metastases.

When they compared transcript and protein expression profiles in tumor samples from metastatic and non-metastatic cases, the researchers saw altered levels for eight transcription factors, particularly expression shifts that appeared to stem from copy number variation.

The team whittled that set down to the top four transcription factors, based on available downstream data, before going on to pinpoint lncRNAs suspected of helping to regulate the transcription factors. They also identified candidate biomarkers for metastases, as well as thousands of potential target genes for the transcription factors. The latter set was enriched for genes from pathways that include WNT signaling, RAS signal transduction, cell migration, and other processes previously implicated in the metastases of other tumor types.

"[O]ur research comprehensively demonstrated the intrinsic functions of four transcription factors in colorectal cancer metastasis, which may extend our knowledge on the underlying mechanisms," the authors concluded, noting that "the strategies and methods in our analyses can serve as a paradigm for relevant cancer studies."