Abstract
Colorectal cancer (CRC) is one of the major causes of cancer deaths across the world. Patients’ survival at time of diagnosis depends mainly on stage of the tumor. Therefore, understanding the molecular mechanisms from low-grade to high-grade stages of cancer that lead to cellular migration from one tissue/organ to another tissue/organ is essential for implementing therapeutic approaches. To this end, we performed a unique meta-analysis flowchart by identifying differentially expressed genes (DEGs) between normal, primary (primary sites), and metastatic samples (Colorectal metastatic lesions in liver and lung) in some Test datasets. DEGs were employed to construct a protein-protein interaction (PPI) network. A smaller network containing 39 DEGs was then extracted from the PPI network whose nodes expression induction or suppression alone or in combination with each other would inhibit tumor progression or metastasis. These DEGs were then verified by gene expression profiling, survival analysis, and multiple Validation datasets. We suggested for the first time that downregulation of mitochondrial genes, including ETHE1, SQOR, TST, and GPX3, would help colorectal cancer cells to produce more energy under hypoxic conditions through mechanisms that are different from “Warburg Effect”. Augmentation of given antioxidants and repression of P4HA1 and COL1A2 genes could be a choice of CRC treatment. Moreover, promoting active GSK-3β together with expression control of EIF2B would prevent EMT. We also proposed that OAS1 expression enhancement can induce the anti-cancer effects of interferon-gamma, while suppression of CTSH hinders formation of focal adhesions. ATF5 expression suppression sensitizes cancer cells to anchorage-dependent death signals, while LGALS4 induction recovers cell-cell junctions. These inhibitions and inductions would be another combinatory mechanism that inhibits EMT and cell migration. Furthermore, expression inhibition of TMPO, TOP2A, RFC3, GINS1, and CKS2 genes could prevent tumor growth. Besides, TRIB3 suppression would be a promising target for anti−angiogenic therapy. SORD is a poorly studied enzyme in cancer, found to be upregulated in CRC. Finally, TMEM131 and DARS genes were identified in this study whose roles have never been interrogated in any kind of cancer, neither as a biomarker nor curative target. All the mentioned mechanisms must be further validated by experimental wet-lab techniques.
Highlights
Colorectal cancer (CRC) is a major global medical burden worldwide [1]
We looked for the unknown key factors that partially control one or more steps of cancer progression, including cell proliferation, transformation, angiogenesis, and metastasis to the distant secondary sites
Some samples in the PCA plane lay at a distance from their group, along the PC1 axis, so they were considered as the outliers
Summary
Colorectal cancer (CRC) is a major global medical burden worldwide [1]. Approximately more than one million people are diagnosed with CRC each year, and about half of them die of CRC annually [2]. Complex genetic interactions are combined with environmental factors to trigger a cell to become cancerous. Contrary to early-stage tumor cells, malignant cells have the ability to detach from the stroma as well as acquire motility [3]. This event happens during a process called Epithelial-Mesenchymal Transition (EMT), in which cells lose their epithelial characteristic, including adhesion, and subsequently dedifferentiate into mesenchymal mobile cells [4]. Investigating DEGs between primary and metastatic sites of tumors would aim to recognize key factors playing roles in cell migration. While primary sites were non-malignant colon biopsies in Test datasets, CRC metastatic sites were located on the other organs
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