Expression of Krüppel like factor 8 in breast cancer and its clinical significances_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAI Yangyang ¹ , SHI Xinpeng ^2,3 ,  LUO Xiaoyong ^2,3

1. Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, P. R. China;
2. Department of Radiotherapy, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471009, P. R. China;
3. Luoyang Cancer Clinical Diagnosis and Treatment Research Center, Luoyang, Henan 471009, P. R. China;

Corresponding author：

LUO Xiaoyong, Email: zlklxy68@163.com

Keywords：

breast cancer; Krüppel like factor 8; cellular localization; clinicopathologic features; prognosis

DOI：

10.7507/1007-9424.202102004

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Objective To detect the expression of Krüppel like factor 8 (KLF8) in breast cancer tissues and cells and to explore the clinical significance of KLF8.Methods ① The Oncomine database was used to analyze the differential expression of KLF8 mRNA in the breast cancer tissues. The Kaplan-Meier Plotter database was used to analyze the relationship between KLF8 mRNA expression and prognosis (relapse free survival, overall survival, post-progression survival, and distant metastasis-free survival) of patients with breast cancer. ② The quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the KLF8 expression levels in the 16 clinical patients with breast cancer and 7 breast cancer cell lines (MDA-MB-231, MCF-12A, Hs-578T, MCF-7, BT-474, MDA-MB-453, ZR-75-30) and normal breast epithelial cell lines MCF-10A, and the immunofluorescence was used to further detect the localization of KLF8 expression in the 2 breast cancer cell lines with higher KLF8 expression level. ③ The immunohistochemistry was used to detect the expression of KLF8 protein in 135 cases of breast cancer tissue microarrays, and the relationships between KLF8 protein expression and clinicopathologic characteristics or overall survival were analyzed.Results ① The Oncomine database showed that KLF8 mRNA expression in the breast cancer tissues was higher than that in the normal breast tissues (P<0.001). The median KLF8 mRNA expression level was taken as the cut-off point for high or low KLF8 expression. The results of Kaplan-Meier Plotter data analysis showed that the prognosis (relapse free survival, overall survival, postprogression survival, and distant metastasis-free survival) of patients with low KLF8 mRNA expression were better than those of patients with high KLF8 mRNA expression (P<0.05). ② The results of qRT-PCR and Western blot all showed that the KLF8 mRNA and protein expression levels in the breast cancer tissues were higher than those in the adjacent normal tissues (P=0.002, P<0.001). In addition, the Western blot results showed that the expression of KLF8 protein in the 7 breast cancer cell lines was higher than that in the normal breast epithelial cell lines MCF-10A respectively, and KLF8 protein mainly expressed in the cytoplasm of breast cancer cells and highly expressed in the nuclear of a few cells. ③ There were 63 cases of high KLF8 expression and 72 cases of low KLF8 expression by the immunohistochemical analysis of 135 patients with breast cancer tissue microarray (the H-score of the immunohistochemical test results was 75 as the cut-off point, H-score >75 was the high KLF8 expression and H-score ≤75 was the low KLF8 expression), the differences of statuses of estrogen receptor (ER) and progesterone receptor (PR) between the patient with high KLF8 expression and low KLF8 expression were significant (P<0.05). The Kaplan-Meier survival curve analysis showed that the prognosis of patients with high KLF8 expression was worse than that of patients with low KLF8 expression (P=0.002). The univariate analysis showed that the TNM stage, statuses of ER and PR, and KLF8 expression were related to the prognosis of patients with breast cancer (P<0.05), further multivariate Cox proportional hazards regression analysis indicated that the later stage of TNM and high KLF8 expression were the independent risk factors (P<0.05).Conclusions The results of this study suggest that KLF8 highly expresses in both breast cancer tissues and breast cancer cells, which is related to the statuses of ER and PR and prognosis of patients with breast cancer. KLF8 might be involved in the progression of breast cancer as an oncogenic gene, or it might provide a new direction for prognosis judgment and molecular targeted therapy of breast cancer.

Citation： ZHAI Yangyang, SHI Xinpeng, LUO Xiaoyong. Expression of Krüppel like factor 8 in breast cancer and its clinical significances. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(10): 1320-1327. doi: 10.7507/1007-9424.202102004 Copy

1.	陈万青, 郑荣寿. 中国女性乳腺癌发病死亡和生存状况. 中国肿瘤临床, 2015, 42(13): 668-674.
2.	杜建姝. 中国乳腺癌现状. 世界最新医学信息文摘, 2019, 19(46): 371-372.
3.	McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev, 2010, 90(4): 1337-1381.
4.	Kaczynski J, Cook T, Urrutia R. Sp1- and Krüppel-like transcription factors. Genome Biol, 2003, 4(2): 206.
5.	Zhang J, Li G, Feng L, et al. Krüppel-like factors in breast cancer: Function, regulation and clinical relevance. Biomed Pharmacother, 2020, 123: 109778.
6.	Wang MD, Xing H, Li C, et al. A novel role of Kruppel-like factor 8 as an apoptosis repressor in hepatocellular carcinoma. Cancer Cell Int, 2020, 20: 422.
7.	Yan Q, Zhang W, Wu Y, et al. KLF8 promotes tumorigenesis, invasion and metastasis of colorectal cancer cells by transcriptional activation of FHL2. Oncotarget, 2015, 6(28): 25402-25417.
8.	Ma D, Liu H, Qin Y, et al. KLF8 overexpression promotes the growth of human lung cancer cells by promoting the expression of JMJD2A. Cancer Cell Int, 2019, 19: 258.
9.	Mao A, Zhou X, Liu Y, et al. KLF8 is associated with poor prognosis and regulates glycolysis by targeting GLUT4 in gastric cancer. J Cell Mol Med, 2019, 23(8): 5087-5097.
10.	Wang X, Zheng M, Liu G, et al. Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res, 2007, 67(15): 7184-7193.
11.	Wang X, Lu H, Urvalek AM, et al. KLF8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of MMP9. Oncogene, 2011, 30(16): 1901-1911.
12.	Lu H, Hu L, Yu L, et al. KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer. Oncogene, 2014, 33(22): 2909-2917.
13.	Li T, Lu H, Shen C, et al. Identification of epithelial stromal interaction 1 as a novel effector downstream of Krüppel-like factor 8 in breast cancer invasion and metastasis. Oncogene, 2014, 33(39): 4746-4755.
14.	Cojoc M, Peitzsch C, Trautmann F, et al. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther, 2013, 6: 1347-1361.
15.	翟秧秧, 师鑫鹏, 罗晓勇. Krüppell 样转录因子 8 在乳腺癌中的研究进展. 癌症进展, 2020, 18(23): 2382-2385, 2391.
16.	Lu H, Hu L, Li T, et al. A novel role of Krüppel-like factor 8 in DNA repair in breast cancer cells. J Biol Chem, 2012, 287(52): 43720-43729.
17.	Li T, Lu H, Mukherjee D, et al. Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer. Oncotarget, 2015, 6(25): 21428-21442.
18.	Mehta TS, Lu H, Wang X, et al. A unique sequence in the N-terminal regulatory region controls the nuclear localization of KLF8 by cooperating with the C-terminal zinc-fingers. Cell Res, 2009, 19(9): 1098-1109.
19.	Lahiri SK, Lu H, Mukherjee D, et al. ERK2 phosphorylates Krüppel-like factor 8 protein at serine 48 to maintain its stability. Am J Cancer Res, 2016, 6(5): 910-923.
20.	Li JC, Yang XR, Sun HX, et al. Up-regulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology, 2010, 139(6): 2146-2157.
21.	Shi X, Luo X, Yan Q, et al. Suppression of KLF8 induces cell differentiation and sensitizes colorectal cancer to 5-fluorouracil. Oncol Rep, 2015, 34(3): 1221-1230.
22.	Schnell O, Romagna A, Jaehnert I, et al. Krüppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation. PLoS One, 2012, 7(1): e30429.
23.	Wei Y, Chen G, You L, et al. Krüpel-like factor 8 is a potential prognostic factor for pancreatic cancer. Chin Med J (Engl), 2014, 127(5): 856-859.
24.	Hsu LS, Wu PR, Yeh KT, et al. Positive nuclear expression of KLF8 might be correlated with shorter survival in gastric adenocarcinoma. Ann Diagn Pathol, 2014, 18(2): 74-77.
25.	Pandya AY, Talley LI, Frost AR, et al. Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res, 2004, 10(8): 2709-2719.
26.	Chen CJ, Lin SE, Lin YM, et al. Association of expression of Krüppel-like factor 4 and kruppel-like factor 5 with the clinical manifestations of breast cancer. Pathol Oncol Res, 2012, 18(2): 161-168.
27.	Akaogi K, Nakajima Y, Ito I, et al. KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha. Oncogene, 2009, 28(32): 2894-2902.
28.	Liu J, Du T, Yuan Y, et al. KLF6 inhibits estrogen receptor-mediated cell growth in breast cancer via a c-Src-mediated pathway. Mol Cell Biochem, 2010, 335(1-2): 29-35.

1. 陈万青, 郑荣寿. 中国女性乳腺癌发病死亡和生存状况. 中国肿瘤临床, 2015, 42(13): 668-674.
2. 杜建姝. 中国乳腺癌现状. 世界最新医学信息文摘, 2019, 19(46): 371-372.
3. McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev, 2010, 90(4): 1337-1381.
4. Kaczynski J, Cook T, Urrutia R. Sp1- and Krüppel-like transcription factors. Genome Biol, 2003, 4(2): 206.
5. Zhang J, Li G, Feng L, et al. Krüppel-like factors in breast cancer: Function, regulation and clinical relevance. Biomed Pharmacother, 2020, 123: 109778.
6. Wang MD, Xing H, Li C, et al. A novel role of Kruppel-like factor 8 as an apoptosis repressor in hepatocellular carcinoma. Cancer Cell Int, 2020, 20: 422.
7. Yan Q, Zhang W, Wu Y, et al. KLF8 promotes tumorigenesis, invasion and metastasis of colorectal cancer cells by transcriptional activation of FHL2. Oncotarget, 2015, 6(28): 25402-25417.
8. Ma D, Liu H, Qin Y, et al. KLF8 overexpression promotes the growth of human lung cancer cells by promoting the expression of JMJD2A. Cancer Cell Int, 2019, 19: 258.
9. Mao A, Zhou X, Liu Y, et al. KLF8 is associated with poor prognosis and regulates glycolysis by targeting GLUT4 in gastric cancer. J Cell Mol Med, 2019, 23(8): 5087-5097.
10. Wang X, Zheng M, Liu G, et al. Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res, 2007, 67(15): 7184-7193.
11. Wang X, Lu H, Urvalek AM, et al. KLF8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of MMP9. Oncogene, 2011, 30(16): 1901-1911.
12. Lu H, Hu L, Yu L, et al. KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer. Oncogene, 2014, 33(22): 2909-2917.
13. Li T, Lu H, Shen C, et al. Identification of epithelial stromal interaction 1 as a novel effector downstream of Krüppel-like factor 8 in breast cancer invasion and metastasis. Oncogene, 2014, 33(39): 4746-4755.
14. Cojoc M, Peitzsch C, Trautmann F, et al. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther, 2013, 6: 1347-1361.
15. 翟秧秧, 师鑫鹏, 罗晓勇. Krüppell 样转录因子 8 在乳腺癌中的研究进展. 癌症进展, 2020, 18(23): 2382-2385, 2391.
16. Lu H, Hu L, Li T, et al. A novel role of Krüppel-like factor 8 in DNA repair in breast cancer cells. J Biol Chem, 2012, 287(52): 43720-43729.
17. Li T, Lu H, Mukherjee D, et al. Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer. Oncotarget, 2015, 6(25): 21428-21442.
18. Mehta TS, Lu H, Wang X, et al. A unique sequence in the N-terminal regulatory region controls the nuclear localization of KLF8 by cooperating with the C-terminal zinc-fingers. Cell Res, 2009, 19(9): 1098-1109.
19. Lahiri SK, Lu H, Mukherjee D, et al. ERK2 phosphorylates Krüppel-like factor 8 protein at serine 48 to maintain its stability. Am J Cancer Res, 2016, 6(5): 910-923.
20. Li JC, Yang XR, Sun HX, et al. Up-regulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology, 2010, 139(6): 2146-2157.
21. Shi X, Luo X, Yan Q, et al. Suppression of KLF8 induces cell differentiation and sensitizes colorectal cancer to 5-fluorouracil. Oncol Rep, 2015, 34(3): 1221-1230.
22. Schnell O, Romagna A, Jaehnert I, et al. Krüppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation. PLoS One, 2012, 7(1): e30429.
23. Wei Y, Chen G, You L, et al. Krüpel-like factor 8 is a potential prognostic factor for pancreatic cancer. Chin Med J (Engl), 2014, 127(5): 856-859.
24. Hsu LS, Wu PR, Yeh KT, et al. Positive nuclear expression of KLF8 might be correlated with shorter survival in gastric adenocarcinoma. Ann Diagn Pathol, 2014, 18(2): 74-77.
25. Pandya AY, Talley LI, Frost AR, et al. Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res, 2004, 10(8): 2709-2719.
26. Chen CJ, Lin SE, Lin YM, et al. Association of expression of Krüppel-like factor 4 and kruppel-like factor 5 with the clinical manifestations of breast cancer. Pathol Oncol Res, 2012, 18(2): 161-168.
27. Akaogi K, Nakajima Y, Ito I, et al. KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha. Oncogene, 2009, 28(32): 2894-2902.
28. Liu J, Du T, Yuan Y, et al. KLF6 inhibits estrogen receptor-mediated cell growth in breast cancer via a c-Src-mediated pathway. Mol Cell Biochem, 2010, 335(1-2): 29-35.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression of Krüppel like factor 8 in breast cancer and its clinical significances

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