Promotes Colorectal Cancer Liver Metastasis by Enhancing the Growth of Metastatic Cancer Cells Via a Fatty Acids-dependent Manner

Overview

Journal J Gastrointest Oncol

Date 2024 Jan 10

PMID 38196537

Authors

Lei Jin

Ju Huang

Lei Guo

Bo Zhang

Qin Li

Hui Li

Mincheng Yu

Peiyi Xie

Qiang Yu

Zheng Chen

Shuang Liu

Yongfeng Xu

Yongsheng Xiao

Ming Lu

Qinghai Ye

Affiliations

Soon will be listed here.

Abstract

Background: Liver metastasis (LM) accounts for most colorectal cancer (CRC)-related deaths. However, how metastatic CRC cells gain the ability to survive and grow in liver remains largely unknown.

Methods: First, we screened differentially expressed genes (DEGs) between LM and paired primary tumors (PTs) in Gene Expression Omnibus (GEO) database, and identified cytochrome P450 1B1 ( as the only common differential gene. Then, we verified messenger RNA (mRNA) and protein expression level in clinical specimens. After constructing stable up-regulated versions of HCT116 and RKO CRC cells and stable down-regulated CYP1B1 versions of SW480 and HT29 CRC cells, cell proliferation assays, subcutaneous tumor formation, and mouse LM models were used to comprehend its function. Next, we used RNA-seq to uncover specific mechanisms of growth; cell cycle, polymerase chain reaction (PCR), western blot (WB) and GEO series (GSE) datasets were used to verify its mechanism. Last, gas chromatography tandem mass spectrometry (GC-MS/MS) was adopted to examine which fatty acids were changed.

Results: A significantly higher level of CYP1B1 was found in LM than in PT in paired clinical CRC LM samples (P<0.05). After CYP1B1 overexpression in HCT116 and RKO cells, cell proliferation abilities and were enhanced; LM of NOD.Cg-PrkdcIl2rg (NSG) mice were enhanced. And knockdown of CYP1B1 in SW480 and HT29 cells, cell proliferation abilities and were reduced; LM of NSG mice were declined (P<0.05). RNA-seq showed 59 common genes from upregulated genes of RKO overexpression group and downregulated genes of SW480 knockdown group were enriched in cell cycle and DNA replication. Further investigation revealed CYP1B1 regulated alternation of , , and genes, and G1/S transition in CRC cells. GC-MS/MS revealed long chain fatty acids (LCFAs) made a difference in SW480 knockdown group (P<0.05). Through adding LCFAs into SW480 and HT29 knockdown groups, cell proliferation abilities and were enhanced, and expressions of , , were upregulated (P<0.05).

Conclusions: exerts a significant influence on LM of CRC by modulating tumor cell proliferation via "CYP1B1-LCFAs-G1/S transition". This finding suggests could be a promising target for CRC LM.

Citing Articles

Low expression of ELOVL6 may be involved in fat loss in white adipose tissue of cancer-associated cachexia.

Jin C, Wang S, Sui X, Meng Q, Wu G Lipids Health Dis. 2024; 23(1):144.

PMID: 38760797 PMC: 11100253. DOI: 10.1186/s12944-024-02126-9.

References

Teng S, Li Y, Yang M, Qi R, Huang Y, Wang Q . Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer. Cell Res. 2019; 30(1):34-49. PMC: 6951341. DOI: 10.1038/s41422-019-0259-z. View

Nordlinger B, Sorbye H, Glimelius B, Poston G, Schlag P, Rougier P . Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013; 14(12):1208-15. DOI: 10.1016/S1470-2045(13)70447-9. View

Badawi A, Cavalieri E, Rogan E . Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism. 2001; 50(9):1001-3. DOI: 10.1053/meta.2001.25592. View

Meng Q, Wang Z, Cui J, Cui Q, Dong J, Zhang Q . Design, Synthesis, and Biological Evaluation of Cytochrome P450 1B1 Targeted Molecular Imaging Probes for Colorectal Tumor Detection. J Med Chem. 2018; 61(23):10901-10909. DOI: 10.1021/acs.jmedchem.8b01633. View

Lin Q, Cao J, Du X, Yang K, Yang X, Liang Z . CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation. Cell Commun Signal. 2022; 20(1):31. PMC: 8922936. DOI: 10.1186/s12964-021-00807-x. View

Patel S, Bhambra U, Charalambous M, David R, Edwards R, Lightfoot T . Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3. Br J Cancer. 2014; 111(12):2287-96. PMC: 4264448. DOI: 10.1038/bjc.2014.540. View

Hwang Y, Won S, Jin S, Lee G, Pham T, Choi J . WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells. Int J Mol Sci. 2019; 20(23). PMC: 6928855. DOI: 10.3390/ijms20235928. View

Narayanan A, Baskaran S, Amalaradjou M, Venkitanarayanan K . Anticarcinogenic properties of medium chain fatty acids on human colorectal, skin and breast cancer cells in vitro. Int J Mol Sci. 2015; 16(3):5014-27. PMC: 4394462. DOI: 10.3390/ijms16035014. View

Jenkyn-Bedford M, Jones M, Baris Y, Labib K, Cannone G, Yeeles J . A conserved mechanism for regulating replisome disassembly in eukaryotes. Nature. 2021; 600(7890):743-747. PMC: 8695382. DOI: 10.1038/s41586-021-04145-3. View

10.

Shah B, Xu W, Mraz J . Cytochrome P450 1B1: role in health and disease and effect of nutrition on its expression. RSC Adv. 2022; 9(36):21050-21062. PMC: 9065998. DOI: 10.1039/c9ra03674a. View

11.

Yang L, Ma C, Zhang L, Zhang M, Li F, Zhang C . 15-Lipoxygenase-2/15(S)-hydroxyeicosatetraenoic acid regulates cell proliferation and metastasis via the STAT3 pathway in lung adenocarcinoma. Prostaglandins Other Lipid Mediat. 2018; 138:31-40. DOI: 10.1016/j.prostaglandins.2018.07.003. View

12.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

13.

Grippo V, Mojovic M, Pavicevic A, Kabelac M, Hubatka F, Turanek J . Electrophilic characteristics and aqueous behavior of fatty acid nitroalkenes. Redox Biol. 2020; 38:101756. PMC: 7658499. DOI: 10.1016/j.redox.2020.101756. View

14.

Baris Y, Taylor M, Aria V, Yeeles J . Fast and efficient DNA replication with purified human proteins. Nature. 2022; 606(7912):204-210. PMC: 7613936. DOI: 10.1038/s41586-022-04759-1. View

15.

Kwon Y, Baek H, Ye D, Shin S, Kim D, Chun Y . CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/β-Catenin Signaling via Sp1 Upregulation. PLoS One. 2016; 11(3):e0151598. PMC: 4794175. DOI: 10.1371/journal.pone.0151598. View

16.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

17.

Elbekai R, El-Kadi A . Cytochrome P450 enzymes: central players in cardiovascular health and disease. Pharmacol Ther. 2006; 112(2):564-87. DOI: 10.1016/j.pharmthera.2005.05.011. View

18.

Hoving L, Heijink M, van Harmelen V, Willems van Dijk K, Giera M . GC-MS Analysis of Medium- and Long-Chain Fatty Acids in Blood Samples. Methods Mol Biol. 2018; 1730:257-265. DOI: 10.1007/978-1-4939-7592-1_18. View

19.

Larsen M, Bushkofsky J, Gorman T, Adhami V, Mukhtar H, Wang S . Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis. Arch Biochem Biophys. 2015; 571:21-39. PMC: 4387869. DOI: 10.1016/j.abb.2015.02.010. View

20.

Rzechorzek N, Hardwick S, Jatikusumo V, Chirgadze D, Pellegrini L . CryoEM structures of human CMG-ATPγS-DNA and CMG-AND-1 complexes. Nucleic Acids Res. 2020; 48(12):6980-6995. PMC: 7337937. DOI: 10.1093/nar/gkaa429. View