Forkhead box A2 Promotes Colorectal Cancer Progression and Targets BCL2-Associated X (BAX) Protein
Abstract
Background: Colorectal cancer is the third most common malignant tumor in the world and substantial death cases are reported each year. We aimed to explore the molecular mechanism underlying colorectal cancer tumorigenesis and progression.
Methods: The expression levels of Forkhead box A2 (FOXA2) in colorectal cancer tissues were first analyzed using Gene Expression Profiling Interactive Analysis (GEPIA). More multiple in vitro experiments established the role of FOXA2 in colorectal cancer progression. The potential downstream target of FOXA2 was identified by Western blot analysis.
Results: FOXA2 expression level was significantly up-modulated in colorectal cancer specimens and cells (P<0.05). Silencing FOXA2 remarkably inhibited colorectal cancer cells growth, invasion and migration. BCL2-associated X (BAX) protein was identified as a potential downstream protein of FOXA2.
Conclusion: Our findings demonstrated the essential role of FOXA2 in colorectal cancer progression and identified BAX protein as its potential target.
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16. Song Y, Washington MK, Crawford HC (2010). Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res, 70:2115-25.
17. Kaestner KH (2010). The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev, 20:527-32.
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21. Jansson A, Sun XF (2002). Bax expression decreases significantly from primary tumor to metastasis in colorectal cancer. J Clin Oncol, 20:811-6.
22. Dong H, Wang W, Chen R, et al (2018). Exosome-mediated transfer of lncRNASNHG14 promotes trastuzumab chemoresistance in breast cancer. Int J Oncol, 53:1013-1026.
23. Liu X, Dong J, Cai W, Pan Y, Li R, Li B (2017). The Effect of Thymoquinone on Apoptosis of SK-OV-3 Ovarian Cancer Cell by Regulation of Bcl-2 and Bax. Int J Gynecol Cancer, 27:1596-1601.
24. Jang SM, An JH, Kim CH, Kim JW, Choi KH (2015). Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. Biochem Biophys Res Commun, 463:961-7.
25. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 45:W98-W102.
26. Pompsch M, Vogel J, Classen F, et al (2018). The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia. BMC Cancer, 18:1190.
27. Hirano S (2012). Western blot analysis. Methods Mol Biol, 926:87-97.
28. Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M (2013). Cancer genetics and genomics of human FOX family genes. Cancer Lett, 328:198-206.
29. Perez-Herrero E, Fernandez-Medarde A (2015). Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm, 93:52-79.
30. Chen SY, Ma DN, Chen QD, et al (2017). MicroRNA-200a inhibits cell growth and metastasis by targeting Foxa2 in hepatocellular carcinoma. J Cancer, 8:617-625.
31. Rokavec M, Oner MG, Li H, et al (2014). IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest, 124:1853-67.
32. Lan J, Sun L, Xu F, et al (2019). M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer. Cancer Res, 79:146-158.
33. Friedl P, Wolf K (2003). Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer, 3:362-74.
34. Liu Q, Pang J, Wang LA, et al (2021). Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2. J Pathol, 253:106-118.
35. Bow YD, Wang YY, Chen YK, et al (2020). Silencing of FOXA2 decreases E-cadherin expression and is associated with lymph node metastasis in oral cancer. Oral Dis, 26:756-765.
36. Pryczynicz A, Gryko M, Niewiarowska K, Cepowicz D, Ustymowicz M, Kemona A, Guzinska-Ustymowicz K (2014). Bax protein may influence the invasion of colorectal cancer. World J Gastroenterol, 20:1305-10.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 68:394-424.
3. Siegel RL, Miller KD, Jemal A (2019). Cancer statistics, 2019. CA Cancer J Clin, 69:7-34.
4. Katoh M, Katoh M (2004). Human FOX gene family (Review). Int J Oncol, 25:1495-500.
5. Ploton M, Mazuy C, Gheeraert C, et al (2018). The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis. J Hepatol, 69:1099-1109.
6. Dhakal P, Kelleher AM, Behura SK, Spencer TE (2020). Sexually dimorphic effects of forkhead box a2 (FOXA2) and uterine glands on decidualization and fetoplacental development. Proc Natl Acad Sci U S A, 117:23952-23959.
7. Bochkis IM, Rubins NE, White P, Furth EE, Friedman JR, Kaestner KH (2008). Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med, 14:828-36.
8. Li CM, Gocheva V, Oudin MJ, et al (2015). Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Genes Dev, 29:1850-62.
9. Tang Y, Shu G, Yuan X, Jing N, Song J (2011). FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell Res, 21:316-26.
10. Chu GC, Zhau HE, Wang R, et al (2014). RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocr Relat Cancer, 21:311-26.
11. Ozaki T, Matsubara T, Seo D, et al (2012). Thyroid regeneration: characterization of clear cells after partial thyroidectomy. Endocrinology, 153:2514-25.
12. Zhang Z, Yang C, Gao W, et al (2015). FOXA2 attenuates the epithelial to mesenchymal transition by regulating the transcription of E-cadherin and ZEB2 in human breast cancer. Cancer Lett, 361:240-50.
13. Cao L, Gibson JD, Miyamoto S, et al (2011). Intestinal lineage commitment of embryonic stem cells. Differentiation, 81:1-10.
14. Kaestner KH (2005). The making of the liver: developmental competence in foregut endoderm and induction of the hepatogenic program. Cell Cycle, 4:1146-8.
15. Perez-Balaguer A, Ortiz-Martinez F, Garcia-Martinez A, et al (2015). FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma. Breast Cancer Res Treat, 153:465-74.
16. Song Y, Washington MK, Crawford HC (2010). Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res, 70:2115-25.
17. Kaestner KH (2010). The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev, 20:527-32.
18. Friedman JR, Kaestner KH (2006). The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci, 63:2317-28.
19. Reyna DE, Garner TP, Lopez A, et al (2017). Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. Cancer Cell, 32:490-505 e10.
20. Liu Z, Ding Y, Ye N, Wild C, Chen H, Zhou J (2016). Direct Activation of Bax Protein for Cancer Therapy. Med Res Rev, 36:313-41.
21. Jansson A, Sun XF (2002). Bax expression decreases significantly from primary tumor to metastasis in colorectal cancer. J Clin Oncol, 20:811-6.
22. Dong H, Wang W, Chen R, et al (2018). Exosome-mediated transfer of lncRNASNHG14 promotes trastuzumab chemoresistance in breast cancer. Int J Oncol, 53:1013-1026.
23. Liu X, Dong J, Cai W, Pan Y, Li R, Li B (2017). The Effect of Thymoquinone on Apoptosis of SK-OV-3 Ovarian Cancer Cell by Regulation of Bcl-2 and Bax. Int J Gynecol Cancer, 27:1596-1601.
24. Jang SM, An JH, Kim CH, Kim JW, Choi KH (2015). Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. Biochem Biophys Res Commun, 463:961-7.
25. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 45:W98-W102.
26. Pompsch M, Vogel J, Classen F, et al (2018). The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia. BMC Cancer, 18:1190.
27. Hirano S (2012). Western blot analysis. Methods Mol Biol, 926:87-97.
28. Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M (2013). Cancer genetics and genomics of human FOX family genes. Cancer Lett, 328:198-206.
29. Perez-Herrero E, Fernandez-Medarde A (2015). Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm, 93:52-79.
30. Chen SY, Ma DN, Chen QD, et al (2017). MicroRNA-200a inhibits cell growth and metastasis by targeting Foxa2 in hepatocellular carcinoma. J Cancer, 8:617-625.
31. Rokavec M, Oner MG, Li H, et al (2014). IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest, 124:1853-67.
32. Lan J, Sun L, Xu F, et al (2019). M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer. Cancer Res, 79:146-158.
33. Friedl P, Wolf K (2003). Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer, 3:362-74.
34. Liu Q, Pang J, Wang LA, et al (2021). Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2. J Pathol, 253:106-118.
35. Bow YD, Wang YY, Chen YK, et al (2020). Silencing of FOXA2 decreases E-cadherin expression and is associated with lymph node metastasis in oral cancer. Oral Dis, 26:756-765.
36. Pryczynicz A, Gryko M, Niewiarowska K, Cepowicz D, Ustymowicz M, Kemona A, Guzinska-Ustymowicz K (2014). Bax protein may influence the invasion of colorectal cancer. World J Gastroenterol, 20:1305-10.
| Files | ||
| Issue | Vol 52 No 2 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i2.11883 | |
| Keywords | ||
| Colorectal cancer FOXA2 protein BCL-2-associated X protein Invasion Migration | ||
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How to Cite
1.
Zeng X, Yang X, Parhatsayim S, Abudoukelimu A, Shu Y, Zhao Z. Forkhead box A2 Promotes Colorectal Cancer Progression and Targets BCL2-Associated X (BAX) Protein. Iran J Public Health. 2023;52(2):306-314.
