Correlations of among cadual homeobox gene 2, hypoxia inducible factor<b>-</b>1α protein expressions, and tumor budding in colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHENG Jianbao ¹ , HAN Yang ² , DONG Zepeng ¹ , YU Junhui ¹ ,  SUN Xuejun ¹

1. Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P. R. China;
2. Department of Vascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P. R. China;

Corresponding?author：

SUN Xuejun, Email: sunxy@mail.xjtu.edu.cn

Keywords：

cadual homeobox gene 2; hypoxia inducible factor-1α; tumor budding; colorectal cancer

DOI：

10.7507/1007-9424.202302015

Video：

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Objective To investigate the correlations among the cadual homeobox gene 2 (CDX2), hypoxia inducible factor-1α (HIF-1α) protein expressions, and tumor budding in the colorectal cancer (CRC). Methods In this study, 63 CRC specimens surgically removed in the First Affiliated Hospital of Xi’an Jiaotong University from January 2012 to September 2015 were collected. The CDX2 and HIF-1α protein expressions were detected by immunohistochemical staining streptavidin-biotin peroxidase two-step method. The staining and the grade of tumor budding were observed under an optical microscope, and the correlation was analyzed using Spearman test. Results The positive expressions of CDX2 and HIF-1α proteins in the CRC tissues were 35 (55.6%) and 47 (74.6%) cases, respectively, which was a negative correlation in the CRC (r_s=–0.302, P=0.017). The positive expressions of CDX2 and HIF-1α proteins in the tumor budding of colorectal cancer were 21 (51.2%) and 26 (63.4%) cases, respectively, which was also a negative correlation in the tumor budding of CRC (r_s=–0.336, P=0.031), but there was no statistic correlation between the grade of tumor budding and CDX2 or HIF-1α positive protein expression in the CRC (r_s=0.113, P=0.370; r_s=–0.026, P=0.838). Conclusions The positive expression between CDX2 and HIF-1α has a negative correlation in the same CRC specimen and which has a negative correlation in tumor budding. There is no statistic correlation between grade of tumor budding and CDX2 or HIF-1α protein expression in the CRC. Hypoxia environment may be involved in the downregulation of CDX2 level during the malignant progression of CRC.

Citation： ZHENG Jianbao, HAN Yang, DONG Zepeng, YU Junhui, SUN Xuejun. Correlations of among cadual homeobox gene 2, hypoxia inducible factor-1α protein expressions, and tumor budding in colorectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(6): 681-685. doi: 10.7507/1007-9424.202302015 Copy

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2.	Jing X, Yang F, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer, 2019, 18(1): 157. doi: 10.1186/s12943-019-1089-9.
3.	Xia X, Wang S, Ni B, et al. Hypoxic gastric cancer-derived exosomes promote progression and metastasis via miR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene, 2020, 39(39): 6231-6244.
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5.	de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest, 2020, 130(10): 5074-5087.
6.	Lugli A, Zlobec I, Berger MD, et al. Tumour budding in solid cancers. Nat Rev Clin Oncol, 2021, 18(2): 101-115.
7.	Koelzer VH, Zlobec I, Lugli A. Tumor budding in colorectal cancer—ready for diagnostic practice? Hum Pathol, 2016, 47(1): 4-19.
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11.	Tekin B, Kundert P, Yang HH, et al. CDX2 expression in primary skin tumors-case series and review of the literature. Hum Pathol, 2022, 129: 1-10.
12.	Kaimaktchiev V, Terracciano L, Tornillo L, et al. The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastro-intestinal adenocarcinomas. Mod Pathol, 2004, 17(11): 1392-1399.
13.	Hong KD, Lee D, Lee Y, et al. Reduced CDX2 expression predicts poor overall survival in patients with colorectal cancer. Am Surg, 2013, 79(4): 353-360.
14.	Liang K, Zhou G, Zhang Q, et al. Expression of Hippo pathway in colorectal cancer. Saudi J Gastroenterol, 2014, 20(3): 188-194.
15.	Kn?sel T, Chen Y, Hotovy S, et al. Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma. Int J Colorectal Dis, 2012, 27(11): 1391-1399.
16.	Tiwari A, Tashiro K, Dixit A, et al. Loss of HIF1A from pancreatic cancer cells increases expression of PPP1R1B and degradation of p53 to Promote invasion and metastasis. Gastroenterology, 2020, 159(5): 1882-1897.
17.	Guo H, Ci X, Ahmed M, et al. ONECUT2 is a driver of neuro-endocrine prostate cancer. Nat Commun, 2019, 10(1): 278. doi:10.1038/s41467-018-08133-6.
18.	Hua Q, Mi B, Xu F, et al. Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis. Theranostics, 2020, 10(11): 4762-4778.
19.	鄭見寶, 孫學軍, 王煒, 等. HIF-1α與CDX2在結直腸腺癌組織中的表達及意義. 中國普外基礎與臨床雜志, 2010, 17(12): 1265-1269.
20.	Gabbert H, Wagner R, Moll R, et al. Tumor dedifferentiation: an im-portant step in tumor invasion. Clin Exp Metastasis, 1985, 3(4): 257-279.
21.	Shinto E, Mochizuki H, Ueno H, et al. A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci. Histopathology, 2005, 47(1): 25-31.
22.	Prall F. Tumour budding in colorectal carcinoma. Histopathology, 2007, 50(1): 151-162.
23.	Chen K, Collins G, Wang H, et al. Pathological features and prog-nostication in colorectal cancer. Curr Oncol, 2021, 28(6): 5356-5383.
24.	Ozer SP, Barut SG, Ozer B, et al. The relationship between tumor budding and survival in colorectal carcinomas. Rev Assoc Med Bras (1992), 2019, 65(12): 1442-1447.
25.	Mitrovic B, Handley K, Assarzadegan N, et al. Prognostic and predictive value of tumor budding in colorectal cancer. Clin Colorectal Cancer, 2021, 20(3): 256-264.
26.	中華人民共和國國家衛生健康委員會. 中國結直腸癌診療規范(2020年版). 中華外科雜志, 2020, 58(8): 561-585.
27.	Zheng J, Sun X, Wang W, Lu S. Hypoxia-inducible factor-1 alpha modulates the down-regulation of the homeodomain protein CDX2 in colorectal cancer. Oncol Rep, 2010, 24(1): 97-104.
28.	Derbal-Wolfrom L, Pencreach E, Saandi T, et al. Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2. Oncogene, 2013, 32(36): 4313-4318.

1. Stairs DB, Kong J, Lynch JP. Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia. Prog Mol Biol Transl Sci, 2010, 96: 231-270.
2. Jing X, Yang F, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer, 2019, 18(1): 157. doi: 10.1186/s12943-019-1089-9.
3. Xia X, Wang S, Ni B, et al. Hypoxic gastric cancer-derived exosomes promote progression and metastasis via miR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene, 2020, 39(39): 6231-6244.
4. Weng ML, Chen WK, Chen XY, et al. Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression. Nat Commun, 2020, 11(1): 1869. doi: 10.1038/s41467-020-15795-8.
5. de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest, 2020, 130(10): 5074-5087.
6. Lugli A, Zlobec I, Berger MD, et al. Tumour budding in solid cancers. Nat Rev Clin Oncol, 2021, 18(2): 101-115.
7. Koelzer VH, Zlobec I, Lugli A. Tumor budding in colorectal cancer—ready for diagnostic practice? Hum Pathol, 2016, 47(1): 4-19.
8. Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol, 2017, 30(9): 1299-1311.
9. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin, 2020, 70(3): 145-164.
10. 李憲哲, 熊志中, 謝明顥, 等. 腫瘤大小對3 114例Ⅱ期結直腸癌患者預后的影響. 中華結直腸疾病電子雜志, 2021, 10(2): 149-157.
11. Tekin B, Kundert P, Yang HH, et al. CDX2 expression in primary skin tumors-case series and review of the literature. Hum Pathol, 2022, 129: 1-10.
12. Kaimaktchiev V, Terracciano L, Tornillo L, et al. The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastro-intestinal adenocarcinomas. Mod Pathol, 2004, 17(11): 1392-1399.
13. Hong KD, Lee D, Lee Y, et al. Reduced CDX2 expression predicts poor overall survival in patients with colorectal cancer. Am Surg, 2013, 79(4): 353-360.
14. Liang K, Zhou G, Zhang Q, et al. Expression of Hippo pathway in colorectal cancer. Saudi J Gastroenterol, 2014, 20(3): 188-194.
15. Kn?sel T, Chen Y, Hotovy S, et al. Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma. Int J Colorectal Dis, 2012, 27(11): 1391-1399.
16. Tiwari A, Tashiro K, Dixit A, et al. Loss of HIF1A from pancreatic cancer cells increases expression of PPP1R1B and degradation of p53 to Promote invasion and metastasis. Gastroenterology, 2020, 159(5): 1882-1897.
17. Guo H, Ci X, Ahmed M, et al. ONECUT2 is a driver of neuro-endocrine prostate cancer. Nat Commun, 2019, 10(1): 278. doi:10.1038/s41467-018-08133-6.
18. Hua Q, Mi B, Xu F, et al. Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis. Theranostics, 2020, 10(11): 4762-4778.
19. 鄭見寶, 孫學軍, 王煒, 等. HIF-1α與CDX2在結直腸腺癌組織中的表達及意義. 中國普外基礎與臨床雜志, 2010, 17(12): 1265-1269.
20. Gabbert H, Wagner R, Moll R, et al. Tumor dedifferentiation: an im-portant step in tumor invasion. Clin Exp Metastasis, 1985, 3(4): 257-279.
21. Shinto E, Mochizuki H, Ueno H, et al. A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci. Histopathology, 2005, 47(1): 25-31.
22. Prall F. Tumour budding in colorectal carcinoma. Histopathology, 2007, 50(1): 151-162.
23. Chen K, Collins G, Wang H, et al. Pathological features and prog-nostication in colorectal cancer. Curr Oncol, 2021, 28(6): 5356-5383.
24. Ozer SP, Barut SG, Ozer B, et al. The relationship between tumor budding and survival in colorectal carcinomas. Rev Assoc Med Bras (1992), 2019, 65(12): 1442-1447.
25. Mitrovic B, Handley K, Assarzadegan N, et al. Prognostic and predictive value of tumor budding in colorectal cancer. Clin Colorectal Cancer, 2021, 20(3): 256-264.
26. 中華人民共和國國家衛生健康委員會. 中國結直腸癌診療規范(2020年版). 中華外科雜志, 2020, 58(8): 561-585.
27. Zheng J, Sun X, Wang W, Lu S. Hypoxia-inducible factor-1 alpha modulates the down-regulation of the homeodomain protein CDX2 in colorectal cancer. Oncol Rep, 2010, 24(1): 97-104.
28. Derbal-Wolfrom L, Pencreach E, Saandi T, et al. Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2. Oncogene, 2013, 32(36): 4313-4318.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Correlations of among cadual homeobox gene 2, hypoxia inducible factor-1α protein expressions, and tumor budding in colorectal cancer

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