Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.597536/full |
| _version_ | 1819043953785176064 |
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| author | Mehran Piran Mehran Piran Neda Sepahi Afagh Moattari Amir Rahimi Ali Ghanbariasad |
| author_facet | Mehran Piran Mehran Piran Neda Sepahi Afagh Moattari Amir Rahimi Ali Ghanbariasad |
| author_sort | Mehran Piran |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T10:04:59Z |
| format | Article |
| id | doaj.art-9516eac2177c49758320a476d943b4cf |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T10:04:59Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-9516eac2177c49758320a476d943b4cf2022-12-21T19:07:51ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-06-011110.3389/fonc.2021.597536597536Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic TargetsMehran Piran0Mehran Piran1Neda Sepahi2Afagh Moattari3Amir Rahimi4Ali Ghanbariasad5Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, AustraliaDepartment of Bacteriology and Virology, Medical School, Shiraz University of Medical Sciences, Shiraz, IranNoncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, IranDepartment of Bacteriology and Virology, Medical School, Shiraz University of Medical Sciences, Shiraz, IranBioinformatics and Computational Biology Research Center, Shiraz University of Medical Sciences, Shiraz, IranNoncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, IranColorectal 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.597536/fullcolorectal cancercancer progressionEMTmetastasistherapeutic/curative targetsdiagnostic biomarkers |
| spellingShingle | Mehran Piran Mehran Piran Neda Sepahi Afagh Moattari Amir Rahimi Ali Ghanbariasad Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets Frontiers in Oncology colorectal cancer cancer progression EMT metastasis therapeutic/curative targets diagnostic biomarkers |
| title | Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets |
| title_full | Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets |
| title_fullStr | Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets |
| title_full_unstemmed | Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets |
| title_short | Systems Biomedicine of Primary and Metastatic Colorectal Cancer Reveals Potential Therapeutic Targets |
| title_sort | systems biomedicine of primary and metastatic colorectal cancer reveals potential therapeutic targets |
| topic | colorectal cancer cancer progression EMT metastasis therapeutic/curative targets diagnostic biomarkers |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.597536/full |
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