A “metastasis-prone” signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics
Abstract
Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 x 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the ;Connectivity Map' with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC.
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GHK was identified as one of two perturbagens that could significantly reverse the expression of 70% of 54 human genes overexpressed in patients with an aggressive metastatic form of colon cancer.
“In another study that used the cMap, GHK was identified as one of two perturbagens that could significantly reverse the expression of 70% of 54 human genes overexpressed in patients with an aggressive metastatic form of colon cancer.”
From GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes (2015) · cites this paper as [18]
Hong et al. used the Connectivity Map to find molecules that could inhibit metastatic colon cancer; the search produced only two substances able to down-regulate expression of metastatic genes, GHK and securinine; GHK produced the result at 1 micromolar and securinine at 18 micromolar; GHK suppresses RNA production in 70% of 54 human genes overexpressed in cancer patients, including node molecules
“In 2010, Hong et al. used Broad Institute’s Connectivity Map to find molecules that could inhibit metastatic colon cancer. The Connectivity Map contains expression profiles that were evaluated in five cancer cell lines, in response to 1,309 bioactive small molecules. A search through the database produced only two substances that were able to down-regulate expression of “metastatic” genes— two”
From Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data (2018) · cites this paper as [45]
GHK reverses pathological expression of 70% of genes in a gene signature for metastasis-prone colon cancer.
“It has been shown to reverse pathological expression of 70% genes in a gene signature for metastasis-prone colon cancer”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [2]
Out of 1,309 bioactive molecules, GHK and securinine demonstrated the best ability to reverse expression of 54 genes (74 probe set) overexpressed in malignant invasive metastatic colon cancer.
“Out of 1,309 bioactive molecules, GHK and another wound healing agent, securinine, demonstrated the best ability to reverse expression of 54 gene (74 probe set) overexpressed in malignant invasive metastatic colon cancer.”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [2]
GHK reverses expression of genes associated with early stages of aggressive metastatic colon cancer.
“As Hong et al. study indicates, GHK reverses expression of genes associated with early stages of aggressive metastatic colon cancer.”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [2]
In the Hong et al. study, GHK produced suppression of many cancer metastasis genes at 1 micromolar.
“In the Hong et al. study [2], GHK produced suppression of many cancer metastasis genes at 1 micromolar.”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [2]
GHK and securinine promote wound healing, extracellular remodeling, and macrophage activation.
“Both GHK and securinine promote wound healing, extracellular remodeling, and macrophage activation [22].”
From Skin Regenerative and Anti-Cancer Actions of Copper Peptides (2018) · cites this paper as [22]
GHK at 1 micromolar and securinine at 18 micromolar were computer-recommended treatment molecules chosen from 1309 bioactive compounds for aggressive metastatic colon cancer.
“Two wound-healing compounds, GHK at 1 micromolar and securinine at 18 micromolar, were the computer-recommended treatment molecules chosen from 1309 bioactive compounds for the cancer treatment.”
From Skin Regenerative and Anti-Cancer Actions of Copper Peptides (2018) · cites this paper as [22]
GHK and securinine suppress node molecules associated with metastasis such as YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFACTC2, and TGM2.
“The Broad data indicated that the two healing compounds were suppressing such node molecules associated with metastasis such as YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFACTC2, and TGM2.”
From Skin Regenerative and Anti-Cancer Actions of Copper Peptides (2018) · cites this paper as [22]
The Connectivity Map selected GHK from 1,309 bioactive molecules as the best choice to reset diseased gene patterns to a healthier pattern for aggressive metastatic colon cancer.
“The gene analysis computer program selected GHK from 1,309 bioactive molecules as the best choice to reset the diseased gene patterns to a healthier pattern.”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [8]
Hong et al. identified 54 genes associated with aggressive, metastatic human colon cancer.
“In 2010, Hong et al. identified 54 genes associated with aggressive, metastatic, human colon cancer [8].”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [8]
GHK at 1 micromolar and securinine at 18 micromolar significantly reversed the differential expression of the 54 genes associated with aggressive, metastatic human colon cancer.
“The results indicated that two wound healing and skin remodeling molecules, GHK at 1 micromolar and securinine at 18 micromolar, could significantly reverse the differential expression of these genes”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [8]
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- Authors
- Hong, Y., Downey, T., Eu, K. W., Koh, P. K., & Cheah, P. Y.
- Affiliations
- Partek (United States) (US)
- Singapore General Hospital (SG)
- Corresponding author
- Cheah, Peh Yean
- ORCID
- Cheah, Peh Yean
- Venue
- Clinical & Experimental Metastasis
- Published
- 2010-02
- Volume
- 27
- Issue
- 2
- Pages
- 83-90
- ISSN
- 0262-0898 (ISSN-L)
- 1573-7276
- OpenAlex
- W2050245934
- Cited by
- 319
- References
- 25
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 13 · 2023: 14 · 2022: 24 · 2021: 34 · 2020: 39 · 2019: 31 · 2018: 30 · 2017: 26 · 2016: 26 · 2015: 19 · 2014: 17 · 2013: 18 · 2012: 9
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Clinical & Experimental Metastasis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- colorectal cancer, metastasis prediction, gene expression signatures, early-stage cancer, proficient mismatch repair, prognosis, adjuvant chemotherapy, gene expression profiling, YWHAB, MAP3K5, lamin A/C, APP, GNAQ, F3, NFATc2, TGM2, securinine, extracellular matrix remodeling, macrophage activation, wound healing, metastasis suppression
- MeSH terms
- Aged, Aged, 80 and over, China, Female, Humans, Male, Neoplasm Metastasis, Retrospective Studies, Colorectal Neoplasms, Case-Control Studies, Base Pair Mismatch, Gene Expression Profiling
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