Research on mechanism of action of TXNIP/NLRP3 pathway in the occurrence and development of breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 FENG Hailing , FAN Changling , PAN Zhongjun , HE Shengke

Department of Pathology, Danzhou People’s Hospital, Danzhou, Hainan 571700, P. R. China;

Corresponding?author：

FENG Hailing, Email: fengyanz18@163.com

Keywords：

breast cancer; thioredoxin binding protein/nucleotide-binding oligomerization domain-like receptor protein 3 pathway; cell growth; migration; invasion

DOI：

10.7507/1007-9424.202102050

Video：

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Objective To investigate the regulatory mechanism of thioredoxin binding protein (TXNIP)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) pathway in the occurrence and development of breast cancer.Methods The resected 15 cases of breast cancer tissues and their adjacent tissues in our hospital from September 2019 to June 2020 were selected, and the immunohistochemistry was used to detect the expression levels of TXNIP and NLRP3 in breast cancer and its adjacent tissues. Three kinds of breast cancer cell lines (MDA-MB231, MCF-7 and SKBR3) and normal breast epithelial cell line (HMEC) were collected. Western blot was used to detect the relative expression levels of TXNIP and NLRP3 in three kinds of breast cancer cell lines and HMEC cell line. MDA-MB231 cancer cells were divided into blank control group (normal culture without any treatment), TXNIP overexpression group (Ad-TXNIP group, transfected with adenovirus vector carrying TXNIP overexpression sequence), Ad-TXNIP negative control group (Ad-eGFP1 group, transfected of empty adenovirus vector without TXNIP overexpression sequence), NLRP3 overexpression group (Ad-NLRP3 group, transfected with adenovirus vector containing NLRP3 overexpression sequence), TXNIP and NLRP3 overexpression co-transfection group (Ad-TXNIP+Ad-NLRP3 group, co-transfection of adenovirus vector carrying TXNIP and NLRP3 overexpression sequence), TXNIP overexpression and Ad-NLRP3 negative control (Ad-eGFP2) co-transfection group (Ad-TXNIP+Ad-eGFP2 group,co-transfection of adenovirus vector carrying TXNIP overexpression sequence and empty adenovirus without NLRP3 overexpression sequence). After 24 hours of transfection and culture, CCK-8 method was used to detect the MDA-MB231 cells proliferation. Transwell chamber method was used to detect MDA-MB231 cells migration and invasion. Nude mice tumorigenicity test was used to detect the tumorigenicity of the MDA-MB231 cells in vivo. Western blot was used to detect the expressions of TXNIP, NLRP3, proliferation marker protein (Ki-67), caspase-1, vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-18 and caspase-1 precursor protein (pro-caspase-1) in the MDA-MB231 cells.Results Compared with the adjacent tissues, the relative expression level of TXNIP decreased (P<0.05) and the relative expression level of NLRP3 increased (P<0.05) in breast cancer tissues. Compared with normal breast epithelial cell line (HMEC cell line), the relative expression levels of TXNIP in MDA-MB231, MCF-7 and SKBR3 breast cancer cell lines were decreased (P<0.05), and the relative expression levels of NLRP3 were increased (P<0.05). Compared with the blank control group, the relative expression levels of TXNIP, NLRP3, IL-1β, IL-18, pro-caspase-1 and caspase-1 were increased (P<0.05), the relative expression levels of Ki-67 and VEGF, the proliferation activity, invasion and migration ability of MDA-MB231 cells and tumor weight were decreased (P<0.05) in the Ad-TXNIP group and the Ad-NLRP3 group. Compared with the Ad-TXNIP group and the Ad-NLRP3 group, the relative expression levels of TXNIP, NLRP3, IL-1β, IL-18, pro-caspase-1 and caspase-1 were further increased (P<0.05), the relative expression levels of Ki-67 and VEGF, the proliferation activity, invasion and migration ability of MDA-MB231 cells and tumor weight were further decreased (P<0.05) in the Ad-TXNIP+Ad-NLRP3 group.Conclusions In breast cancer tissues and breast cancer cell lines, TXNIP is low expression and NLRP3 is high expression. They can interact with each other to promote pyroptosis and inhibit the proliferation, invasion and migration of breast cancer cells.

Citation： FENG Hailing, FAN Changling, PAN Zhongjun, HE Shengke. Research on mechanism of action of TXNIP/NLRP3 pathway in the occurrence and development of breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(11): 1418-1425. doi: 10.7507/1007-9424.202102050 Copy

1.	Malmgren JA, Calip GS, Atwood MK, et al. Metastatic breast cancer survival improvement restricted by regional disparity: Surveillance, Epidemiology, and End Results and institutional analysis: 1990 to 2011. Cancer, 2020, 126(2): 390-399.
2.	Yin M, Verschraegen C, Vincent VH, et al. Impact of lack of surgery on outcomes in elderly women with nonmetastatic breast cancer–A surveillance, epidemiology, and end results 18 population based study. Medicine (Baltimore), 2020, 99(3): e18745.
3.	Tezcan G, Garanina EE, Zhuravleva MN, et al. Rab GTPase mediating regulation of NALP3 in colorectal cancer. Molecules, 2020, 25(20): 4834.
4.	Yao A, Storr SJ, Al-Hadyan K, et al. Thioredoxin system protein expression is associated with poor clinical outcome in adult and paediatric gliomas and medulloblastomas. Mol Neurobiol, 2020, 57(7): 2889-2901.
5.	Sun X, Wang M, Wang M, et al. Metabolic reprogramming in triple-negative breast cancer. Front Oncol, 2020, 10: 428.
6.	Liu W, Gu J, Qi J, et al. Lentinan exerts synergistic apoptotic effects with paclitaxel in A549 cells via activating ROS-TXNIP-NLRP3 inflammasome. J Cell Mol Med, 2015, 19(8): 1949-1955.
7.	王慧, 趙安帝, 楊謹. 曲妥珠單抗聯合帕妥珠單抗用于HER2陽性早期乳腺癌研究進展. 華中科技大學學報 (醫學版), 2020, 49(1): 111-116.
8.	劉香婷, 屈佳肴, 龔珂, 等. 乳腺癌放療抵抗分子機制研究進展. 山東醫藥, 2020, 60(2): 89-92.
9.	Szpigel A, Hainault I, Carlier A, et al. Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes. Diabetologia, 2018, 61(2): 399-412.
10.	Li Y, Miao LY, Xiao YL, et al. Hypoxia induced high expression of thioredoxin interacting protein (TXNIP) in non-small cell lung cancer and its prognostic effect. Asian Pac J Cancer Prev, 2015, 16(7): 2953-2958.
11.	Jia JJ, Geng WS, Wang ZQ, et al. The role of thioredoxin system in cancer: strategy for cancer therapy. Cancer Chemother Pharmacol, 2019, 84(3): 453-470.
12.	Jovanovi? M, Dragoj M, Zhukovsky D, et al. Novel trxr1 inhibitors show potential for glioma treatment by suppressing the invasion and sensitizing glioma cells to chemotherapy. Front Mol Biosci, 2020, 7: 586146.
13.	Huang G, Pan ST. ROS-mediated therapeutic strategy in chemoradiotherapy of head and neck cancer. Oxid Med Cell Longev, 2020, 2020: 5047987.
14.	Park JW, Lee SH, Woo GH, et al. Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer. Biochem Biophys Res Commun, 2018, 498(3): 566-572.
15.	Cai Z, Zhang C, Zou Y, et al. Tissue thioredoxin-interacting protein expression predicted recurrence in patients with meningiomas. Int J Clin Oncol, 2017, 22(4): 660-666.
16.	Baldan F, Mio C, Lavarone E, et al. Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells. Oncol Rep, 2015, 33(5): 2199-2206.
17.	Iqbal MA, Chattopadhyay S, Siddiqui FA, et al. Silibinin induces metabolic crisis in triple-negative breast cancer cells by modulating EGFR-MYC-TXNIP axis: potential therapeutic implications. FEBS J, 2021, 288(2): 471-485.
18.	Zhang L, Li H, Zang Y, et al. NLRP3 inflammasome inactivation driven by miR-223-3p reduces tumor growth and increases anticancer immunity in breast cancer. Mol Med Rep, 2019, 19(3): 2180-2188.
19.	Ershaid N, Sharon Y, Doron H, et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat Commun, 2019, 10(1): 4375.
20.	曾琬琴, 殷霞, 傅小龍. 細胞焦亡在腫瘤中的研究進展. 腫瘤學雜志, 2020, 26(5): 438-443.
21.	Chen YF, Qi HY, Wu FL. Euxanthone exhibits anti-proliferative and anti-invasive activities in hepatocellular carcinoma by inducing pyroptosis: preliminary results. Eur Rev Med Pharmacol Sci, 2018, 22(23): 8186-8196.
22.	Kofahi HM, Taylor NG, Hirasawa K, et al. Hepatitis C virus infection of cultured human hepatoma cells causes apoptosis and pyroptosis in both infected and bystander cells. Sci Rep, 2016, 6: 37433.

1. Malmgren JA, Calip GS, Atwood MK, et al. Metastatic breast cancer survival improvement restricted by regional disparity: Surveillance, Epidemiology, and End Results and institutional analysis: 1990 to 2011. Cancer, 2020, 126(2): 390-399.
2. Yin M, Verschraegen C, Vincent VH, et al. Impact of lack of surgery on outcomes in elderly women with nonmetastatic breast cancer–A surveillance, epidemiology, and end results 18 population based study. Medicine (Baltimore), 2020, 99(3): e18745.
3. Tezcan G, Garanina EE, Zhuravleva MN, et al. Rab GTPase mediating regulation of NALP3 in colorectal cancer. Molecules, 2020, 25(20): 4834.
4. Yao A, Storr SJ, Al-Hadyan K, et al. Thioredoxin system protein expression is associated with poor clinical outcome in adult and paediatric gliomas and medulloblastomas. Mol Neurobiol, 2020, 57(7): 2889-2901.
5. Sun X, Wang M, Wang M, et al. Metabolic reprogramming in triple-negative breast cancer. Front Oncol, 2020, 10: 428.
6. Liu W, Gu J, Qi J, et al. Lentinan exerts synergistic apoptotic effects with paclitaxel in A549 cells via activating ROS-TXNIP-NLRP3 inflammasome. J Cell Mol Med, 2015, 19(8): 1949-1955.
7. 王慧, 趙安帝, 楊謹. 曲妥珠單抗聯合帕妥珠單抗用于HER2陽性早期乳腺癌研究進展. 華中科技大學學報 (醫學版), 2020, 49(1): 111-116.
8. 劉香婷, 屈佳肴, 龔珂, 等. 乳腺癌放療抵抗分子機制研究進展. 山東醫藥, 2020, 60(2): 89-92.
9. Szpigel A, Hainault I, Carlier A, et al. Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes. Diabetologia, 2018, 61(2): 399-412.
10. Li Y, Miao LY, Xiao YL, et al. Hypoxia induced high expression of thioredoxin interacting protein (TXNIP) in non-small cell lung cancer and its prognostic effect. Asian Pac J Cancer Prev, 2015, 16(7): 2953-2958.
11. Jia JJ, Geng WS, Wang ZQ, et al. The role of thioredoxin system in cancer: strategy for cancer therapy. Cancer Chemother Pharmacol, 2019, 84(3): 453-470.
12. Jovanovi? M, Dragoj M, Zhukovsky D, et al. Novel trxr1 inhibitors show potential for glioma treatment by suppressing the invasion and sensitizing glioma cells to chemotherapy. Front Mol Biosci, 2020, 7: 586146.
13. Huang G, Pan ST. ROS-mediated therapeutic strategy in chemoradiotherapy of head and neck cancer. Oxid Med Cell Longev, 2020, 2020: 5047987.
14. Park JW, Lee SH, Woo GH, et al. Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer. Biochem Biophys Res Commun, 2018, 498(3): 566-572.
15. Cai Z, Zhang C, Zou Y, et al. Tissue thioredoxin-interacting protein expression predicted recurrence in patients with meningiomas. Int J Clin Oncol, 2017, 22(4): 660-666.
16. Baldan F, Mio C, Lavarone E, et al. Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells. Oncol Rep, 2015, 33(5): 2199-2206.
17. Iqbal MA, Chattopadhyay S, Siddiqui FA, et al. Silibinin induces metabolic crisis in triple-negative breast cancer cells by modulating EGFR-MYC-TXNIP axis: potential therapeutic implications. FEBS J, 2021, 288(2): 471-485.
18. Zhang L, Li H, Zang Y, et al. NLRP3 inflammasome inactivation driven by miR-223-3p reduces tumor growth and increases anticancer immunity in breast cancer. Mol Med Rep, 2019, 19(3): 2180-2188.
19. Ershaid N, Sharon Y, Doron H, et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat Commun, 2019, 10(1): 4375.
20. 曾琬琴, 殷霞, 傅小龍. 細胞焦亡在腫瘤中的研究進展. 腫瘤學雜志, 2020, 26(5): 438-443.
21. Chen YF, Qi HY, Wu FL. Euxanthone exhibits anti-proliferative and anti-invasive activities in hepatocellular carcinoma by inducing pyroptosis: preliminary results. Eur Rev Med Pharmacol Sci, 2018, 22(23): 8186-8196.
22. Kofahi HM, Taylor NG, Hirasawa K, et al. Hepatitis C virus infection of cultured human hepatoma cells causes apoptosis and pyroptosis in both infected and bystander cells. Sci Rep, 2016, 6: 37433.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research on mechanism of action of TXNIP/NLRP3 pathway in the occurrence and development of breast cancer

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