Research progress of HtrA serine peptidase 2 in malignant tumors_West China Medical Journal

Authors：

XIONG Yao ¹ ,  FENG Lei ^1,2 , FU Changmin ³ , YAN Ting ³ , WANG huamin ¹ , ZENG Qiuyue ¹

1. Graduate School of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. The Fifth Department of Digestive Disease Center, Suining Central Hospital, Suining, Sichuan 629000, P. R. China;
3. Graduate School of Zunyi Medical University, Zunyi, Guizhou 563000, P. R. China;

Corresponding author：

FENG Lei, Email: 6449880@qq.com

Keywords：

HtrA serine peptidase 2; cell apoptosis; malignant tumor; targeted therapy

DOI：

10.7507/1002-0179.202308182

Video：

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Abstract Full text Figures/Tables Video References Cited by

HtrA serine peptidase 2 (HTRA2) is a serine protease existing in the mitochondrial gap. Among the four members of the human HtrA serine peptidase family, HTRA2 is the only protease with clear localization in the cell. It plays a dual role in the maintenance of mitochondrial homeostasis and the promotion of cell apoptosis. HTRA2 has been found to be associated with a variety of tumors. Meanwhile, the expression of HTRA2 can enhance the sensitivity of chemotherapy and radiotherapy, and can be used as a diagnostic and prognostic marker for malignant tumors and a target for combined therapy. This article reviews the structure, biological function and role of HTRA2 in malignant tumors, in order to provide clues and basis for early diagnosis and individualized treatment of tumor patients.

Citation： XIONG Yao, FENG Lei, FU Changmin, YAN Ting, WANG huamin, ZENG Qiuyue. Research progress of HtrA serine peptidase 2 in malignant tumors. West China Medical Journal, 2024, 39(1): 111-116. doi: 10.7507/1002-0179.202308182 Copy

1.	Faccio L, Fusco C, Chen A, et al. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J Biol Chem, 2000, 275(4): 2581-2588.
2.	Singh S, Datta G, Jain S, et al. Dual role of an essential HtrA2/Omi protease in the human malaria parasite: maintenance of mitochondrial homeostasis and induction of apoptosis-like cell death under cellular stress. PLoS Pathog, 2022, 18(10): e1010932.
3.	Vande Walle L, Lamkanfi M, Vandenabeele P. The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ, 2008, 15(3): 453-460.
4.	Chakraborty A, Bose R, Bose K. Unraveling the dichotomy of enigmatic serine protease HtrA2. Front Mol Biosci, 2022, 9: 824846.
5.	Parui AL, Mishra V, Dutta S, et al. Inter-subunit crosstalk via PDZ synergistically governs allosteric activation of proapoptotic HtrA2. Structure, 2022, 30(9): 1307-1320.
6.	Parui AL, Singh N, Dutta S, et al. Role of conserved regulatory loop residues in allosteric propagation of serine protease HtrA2. Biochem Biophys Res Commun, 2022, 594: 63-68.
7.	Wu L, Liu D, Wu Y, et al. p53 mediated transcription of Omi/HtrA2 in aging myocardium. Biochem Biophys Res Commun, 2019, 519(4): 734-739.
8.	Wang K, Sun M, Juan Z, et al. The improvement of sepsis-associated encephalopathy by P2X7R inhibitor through inhibiting the Omi/HtrA2 apoptotic signaling pathway. Behav Neurol, 2022, 2022: 3777351.
9.	Torii S, Kasai S, Yoshida T, et al. Mitochondrial E3 ubiquitin ligase Parkin: relationships with other causal proteins in familial Parkinson’s disease and its substrate-involved mouse experimental models. Int J Mol Sci, 2020, 21(4): 1202.
10.	Kaur I, Behl T, Sachdeva M, et al. Exploring the mitochondrial apoptotic cell death landscape and associated components serving as molecular targets, primarily for synthetic and natural drugs targeting oncology therapeutics. Curr Mol Pharmacol, 2021, 14(6): 1066-1082.
11.	Edlich F. BCL-2 proteins and apoptosis: recent insights and unknowns. Biochem Biophys Res Commun, 2018, 500(1): 26-34.
12.	DU K, Lu F, Xie C, et al. Toxoplasma gondii infection induces cell apoptosis via multiple pathways revealed by transcriptome analysis. J Zhejiang Univ Sci B, 2022, 23(4): 315-327.
13.	Gambardella S, Ferese R, Scala S, et al. Mitochondrial serine protease HTRA2 p. G399S in a female with Di George syndrome and Parkinson’s disease. Parkinsons Dis, 2018, 2018: 5651435.
14.	Kesavardhana S, Malireddi RKS, Kanneganti TD. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol, 2020, 38: 567-595.
15.	Hanifeh M, Ataei F. XIAP as a multifaceted molecule in cellular signaling. Apoptosis, 2022, 27(7/8): 441-453.
16.	Blink E, Maianski NA, Alnemri ES, et al. Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent cell death of human neutrophils. Cell Death Differ, 2004, 11(8): 937-939.
17.	Chaganti LK, Dutta S, Kuppili RR, et al. Structural modeling and role of HAX-1 as a positive allosteric modulator of human serine protease HtrA2. Biochem J, 2019, 476(20): 2965-2980.
18.	Gao M, Qiu Y, Cao T, et al. Insufficient HtrA2 causes meiotic defects in aging germinal vesicle oocytes. Reprod Biol Endocrinol, 2022, 20(1): 173.
19.	Hur W, Kang BY, Kim SM, et al. Serine protease HtrA2/Omi deficiency impairs mitochondrial homeostasis and promotes hepatic fibrogenesis via activation of hepatic stellate cells. Cells, 2019, 8(10): 1119.
20.	You H, Jin Y, Kang J, et al. Mitochondrial serine protease Omi/HtrA2 accentuates brain ischemia/reperfusion injury in rats and oxidative stress injury in vitro by modulating mitochondrial stress proteins CHOP and ClpP and physically interacting with mitochondrial fusion protein OPA1. Bioengineered, 2020, 11(1): 1058-1070.
21.	Wang H, Jiang F, Hao F, et al. The expression of HtrA2 and its diagnostic value in patients with hepatocellular carcinoma. Medicine (Baltimore), 2018, 97(14): e0128.
22.	Xu Z, Chen X, Peng C, et al. Hypoxia-inducible factor-1alpha suppressed hepatocellular carcinoma cell apoptosis through influencing on Omi/HtrA2 expression and its releasing from the mitochondrion. Oncol Res, 2012, 20(5/6): 213-220.
23.	Feng L, Li Z, Xiong Y, et al. HtrA2 independently predicts poor prognosis and correlates with immune cell infiltration in hepatocellular carcinoma. J Oncol, 2023, 2023: 4067418.
24.	Nho KJ, Chun JM, Kim HK. Induction of mitochondria-dependent apoptosis in HepG2 human hepatocellular carcinoma cells by timosaponin A-III. Environ Toxicol Pharmacol, 2016, 45: 295-301.
25.	Lee SH, Lee JW, Kim HS, et al. Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer. APMIS, 2003, 111(5): 586-590.
26.	Wu L, Li X, Chen X, et al. mRNA microarray profiling identifies a novel circulating HTRA2 for detection of gastric cancer. J Clin Lab Anal, 2021, 35(12): e24054.
27.	刘春灵, 王记红, 高凤兰, 等. Omi/HtrA2 和 Caspase-9 在食管癌中的表达及与凋亡的关系. 中国医学工程, 2016, 24(5): 8-10.
28.	Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, et al. Pancreatic cancer: advances and challenges. Cell, 2023, 186(8): 1729-1754.
29.	Pan L, Zhou L, Yin W, et al. miR-125a induces apoptosis, metabolism disorder and migrationimpairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission. Int J Oncol, 2018, 53(1): 124-136.
30.	Wan J, Cui J, Wang L, et al. Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways. Cancer Cell Int, 2018, 18: 165.
31.	Zurawa-Janicka D, Kobiela J, Slebioda T, et al. Expression of HTRA genes and its association with microsatellite instability and survival of patients with colorectal cancer. Int J Mol Sci, 2020, 21(11): 3947.
32.	Abatay-Sel F, Erol A, Suleymanoglu M, et al. The in vitro treatment of mesenchymal stem cells for colorectal cancer cells. Med Oncol, 2023, 40(3): 103.
33.	Wilkinson L, Gathani T. Understanding breast cancer as a global health concern. Br J Radiol, 2022, 95(1130): 20211033.
34.	罗宇, 刘洪涛, 李医明, 等. HtrA2/Omi 与 Livin 在乳腺浸润性导管癌中表达及其临床意义. 临床军医杂志, 2020, 48(2): 144-148.
35.	Hu Q, Myers M, Fang W, et al. Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion. Biol Open, 2019, 8(7): bio040873.
36.	Thai AA, Solomon BJ, Sequist LV, et al. Lung cancer. Lancet, 2021, 398(10299): 535-554.
37.	Mao G, Lv L, Liu Y, et al. The expression levels and prognostic value of high temperature required A2 (HtrA2) in NSCLC. Pathol Res Pract, 2014, 210(12): 939-943.
38.	Bedhiafi T, Inchakalody VP, Fernandes Q, et al. The potential role of vitamin C in empowering cancer immunotherapy. Biomed Pharmacother, 2022, 146: 112553.
39.	Bieńkowska-Tokarczyk A, Manda-Handzlik A, Gawrychowski K, et al. The activity of vitamin C against ovarian cancer cells is enhanced by hyperthermia. Anticancer Res, 2022, 42(11): 5365-5383.
40.	Ye T, Yao H, Xu Y, et al. Role of Smac, survivin, XIAP, and Omi/HtrA2 proteins in determining the chemotherapeutic response of patients with cervical cancer treated with neoadjuvant chemotherapy. Cancer Biomark, 2019, 26(3): 249-259.
41.	Hu XY, Xu YM, Chen XC, et al. Immunohistochemical analysis of Omi/HtrA2 expression in prostate cancer and benign prostatic hyperplasia. APMIS, 2006, 114(12): 893-898.
42.	Gmeiner WH, Debinski W, Milligan C, et al. The applications of the novel polymeric fluoropyrimidine F10 in cancer treatment: current evidence. Future Oncol, 2016, 12(17): 2009-2020.
43.	Gmeiner WH, Boyacioglu O, Stuart CH, et al. The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn²⁺ -chelation and inhibiting the serine protease Omi/HtrA2. Prostate, 2015, 75(4): 360-369.
44.	李立恒, 周军, 张敏, 等. miR-455 对 Omi/HtrA2 介导的人涎腺腺样囊性癌细胞株线粒体凋亡的影响. 中国老年学杂志, 2022, 42(23): 5839-5844.
45.	及月茹, 陈怡, 李国辉, 等. 急性髓系白血病患者 HtrA2 基因、 Set 基因表达与疗效和预后的关系研究. 现代生物医学进展, 2021, 21(11): 2077-2080.
46.	卞乐, 艾丽梅. 凋亡调节蛋白 XIAP 与 Omi/HtrA2 在弥漫大 B 细胞淋巴瘤中的表达及其与患者预后的关系. 临床荟萃, 2020, 35(5): 438-444.
47.	Chen Q, Qu S, Liang Z, et al. Cathepsin H knockdown reverses radioresistance of hepatocellular carcinoma via metabolic switch followed by apoptosis. Int J Mol Sci, 2023, 24(6): 5257.
48.	Zhang L, Li Y, Li X, et al. Regulation of HtrA2 on WT1 gene expression under imatinib stimulation and its effects on the cell biology of K562 cells. Oncol Lett, 2017, 14(3): 3862-3868.
49.	Cilenti L, Kyriazis GA, Soundarapandian MM, et al. Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. Am J Physiol Renal Physiol, 2005, 288(2): F371-379.
50.	Soyama H, Miyamoto M, Takano M, et al. Ovarian serous carcinomas acquire cisplatin resistance and increased invasion through downregulation of the high-temperature-required protein A2 (HtrA2), following repeated treatment with cisplatin. Med Oncol, 2017, 34(12): 201.
51.	Mahbub AA, Le Maitre CL, Cross NA, et al. The effect of apigenin and chemotherapy combination treatments on apoptosis-related genes and proteins in acute leukaemia cell lines. Sci Rep, 2022, 12(1): 8858.

1. Faccio L, Fusco C, Chen A, et al. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J Biol Chem, 2000, 275(4): 2581-2588.
2. Singh S, Datta G, Jain S, et al. Dual role of an essential HtrA2/Omi protease in the human malaria parasite: maintenance of mitochondrial homeostasis and induction of apoptosis-like cell death under cellular stress. PLoS Pathog, 2022, 18(10): e1010932.
3. Vande Walle L, Lamkanfi M, Vandenabeele P. The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ, 2008, 15(3): 453-460.
4. Chakraborty A, Bose R, Bose K. Unraveling the dichotomy of enigmatic serine protease HtrA2. Front Mol Biosci, 2022, 9: 824846.
5. Parui AL, Mishra V, Dutta S, et al. Inter-subunit crosstalk via PDZ synergistically governs allosteric activation of proapoptotic HtrA2. Structure, 2022, 30(9): 1307-1320.
6. Parui AL, Singh N, Dutta S, et al. Role of conserved regulatory loop residues in allosteric propagation of serine protease HtrA2. Biochem Biophys Res Commun, 2022, 594: 63-68.
7. Wu L, Liu D, Wu Y, et al. p53 mediated transcription of Omi/HtrA2 in aging myocardium. Biochem Biophys Res Commun, 2019, 519(4): 734-739.
8. Wang K, Sun M, Juan Z, et al. The improvement of sepsis-associated encephalopathy by P2X7R inhibitor through inhibiting the Omi/HtrA2 apoptotic signaling pathway. Behav Neurol, 2022, 2022: 3777351.
9. Torii S, Kasai S, Yoshida T, et al. Mitochondrial E3 ubiquitin ligase Parkin: relationships with other causal proteins in familial Parkinson’s disease and its substrate-involved mouse experimental models. Int J Mol Sci, 2020, 21(4): 1202.
10. Kaur I, Behl T, Sachdeva M, et al. Exploring the mitochondrial apoptotic cell death landscape and associated components serving as molecular targets, primarily for synthetic and natural drugs targeting oncology therapeutics. Curr Mol Pharmacol, 2021, 14(6): 1066-1082.
11. Edlich F. BCL-2 proteins and apoptosis: recent insights and unknowns. Biochem Biophys Res Commun, 2018, 500(1): 26-34.
12. DU K, Lu F, Xie C, et al. Toxoplasma gondii infection induces cell apoptosis via multiple pathways revealed by transcriptome analysis. J Zhejiang Univ Sci B, 2022, 23(4): 315-327.
13. Gambardella S, Ferese R, Scala S, et al. Mitochondrial serine protease HTRA2 p. G399S in a female with Di George syndrome and Parkinson’s disease. Parkinsons Dis, 2018, 2018: 5651435.
14. Kesavardhana S, Malireddi RKS, Kanneganti TD. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol, 2020, 38: 567-595.
15. Hanifeh M, Ataei F. XIAP as a multifaceted molecule in cellular signaling. Apoptosis, 2022, 27(7/8): 441-453.
16. Blink E, Maianski NA, Alnemri ES, et al. Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent cell death of human neutrophils. Cell Death Differ, 2004, 11(8): 937-939.
17. Chaganti LK, Dutta S, Kuppili RR, et al. Structural modeling and role of HAX-1 as a positive allosteric modulator of human serine protease HtrA2. Biochem J, 2019, 476(20): 2965-2980.
18. Gao M, Qiu Y, Cao T, et al. Insufficient HtrA2 causes meiotic defects in aging germinal vesicle oocytes. Reprod Biol Endocrinol, 2022, 20(1): 173.
19. Hur W, Kang BY, Kim SM, et al. Serine protease HtrA2/Omi deficiency impairs mitochondrial homeostasis and promotes hepatic fibrogenesis via activation of hepatic stellate cells. Cells, 2019, 8(10): 1119.
20. You H, Jin Y, Kang J, et al. Mitochondrial serine protease Omi/HtrA2 accentuates brain ischemia/reperfusion injury in rats and oxidative stress injury in vitro by modulating mitochondrial stress proteins CHOP and ClpP and physically interacting with mitochondrial fusion protein OPA1. Bioengineered, 2020, 11(1): 1058-1070.
21. Wang H, Jiang F, Hao F, et al. The expression of HtrA2 and its diagnostic value in patients with hepatocellular carcinoma. Medicine (Baltimore), 2018, 97(14): e0128.
22. Xu Z, Chen X, Peng C, et al. Hypoxia-inducible factor-1alpha suppressed hepatocellular carcinoma cell apoptosis through influencing on Omi/HtrA2 expression and its releasing from the mitochondrion. Oncol Res, 2012, 20(5/6): 213-220.
23. Feng L, Li Z, Xiong Y, et al. HtrA2 independently predicts poor prognosis and correlates with immune cell infiltration in hepatocellular carcinoma. J Oncol, 2023, 2023: 4067418.
24. Nho KJ, Chun JM, Kim HK. Induction of mitochondria-dependent apoptosis in HepG2 human hepatocellular carcinoma cells by timosaponin A-III. Environ Toxicol Pharmacol, 2016, 45: 295-301.
25. Lee SH, Lee JW, Kim HS, et al. Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer. APMIS, 2003, 111(5): 586-590.
26. Wu L, Li X, Chen X, et al. mRNA microarray profiling identifies a novel circulating HTRA2 for detection of gastric cancer. J Clin Lab Anal, 2021, 35(12): e24054.
27. 刘春灵, 王记红, 高凤兰, 等. Omi/HtrA2 和 Caspase-9 在食管癌中的表达及与凋亡的关系. 中国医学工程, 2016, 24(5): 8-10.
28. Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, et al. Pancreatic cancer: advances and challenges. Cell, 2023, 186(8): 1729-1754.
29. Pan L, Zhou L, Yin W, et al. miR-125a induces apoptosis, metabolism disorder and migrationimpairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission. Int J Oncol, 2018, 53(1): 124-136.
30. Wan J, Cui J, Wang L, et al. Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways. Cancer Cell Int, 2018, 18: 165.
31. Zurawa-Janicka D, Kobiela J, Slebioda T, et al. Expression of HTRA genes and its association with microsatellite instability and survival of patients with colorectal cancer. Int J Mol Sci, 2020, 21(11): 3947.
32. Abatay-Sel F, Erol A, Suleymanoglu M, et al. The in vitro treatment of mesenchymal stem cells for colorectal cancer cells. Med Oncol, 2023, 40(3): 103.
33. Wilkinson L, Gathani T. Understanding breast cancer as a global health concern. Br J Radiol, 2022, 95(1130): 20211033.
34. 罗宇, 刘洪涛, 李医明, 等. HtrA2/Omi 与 Livin 在乳腺浸润性导管癌中表达及其临床意义. 临床军医杂志, 2020, 48(2): 144-148.
35. Hu Q, Myers M, Fang W, et al. Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion. Biol Open, 2019, 8(7): bio040873.
36. Thai AA, Solomon BJ, Sequist LV, et al. Lung cancer. Lancet, 2021, 398(10299): 535-554.
37. Mao G, Lv L, Liu Y, et al. The expression levels and prognostic value of high temperature required A2 (HtrA2) in NSCLC. Pathol Res Pract, 2014, 210(12): 939-943.
38. Bedhiafi T, Inchakalody VP, Fernandes Q, et al. The potential role of vitamin C in empowering cancer immunotherapy. Biomed Pharmacother, 2022, 146: 112553.
39. Bieńkowska-Tokarczyk A, Manda-Handzlik A, Gawrychowski K, et al. The activity of vitamin C against ovarian cancer cells is enhanced by hyperthermia. Anticancer Res, 2022, 42(11): 5365-5383.
40. Ye T, Yao H, Xu Y, et al. Role of Smac, survivin, XIAP, and Omi/HtrA2 proteins in determining the chemotherapeutic response of patients with cervical cancer treated with neoadjuvant chemotherapy. Cancer Biomark, 2019, 26(3): 249-259.
41. Hu XY, Xu YM, Chen XC, et al. Immunohistochemical analysis of Omi/HtrA2 expression in prostate cancer and benign prostatic hyperplasia. APMIS, 2006, 114(12): 893-898.
42. Gmeiner WH, Debinski W, Milligan C, et al. The applications of the novel polymeric fluoropyrimidine F10 in cancer treatment: current evidence. Future Oncol, 2016, 12(17): 2009-2020.
43. Gmeiner WH, Boyacioglu O, Stuart CH, et al. The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn²⁺ -chelation and inhibiting the serine protease Omi/HtrA2. Prostate, 2015, 75(4): 360-369.
44. 李立恒, 周军, 张敏, 等. miR-455 对 Omi/HtrA2 介导的人涎腺腺样囊性癌细胞株线粒体凋亡的影响. 中国老年学杂志, 2022, 42(23): 5839-5844.
45. 及月茹, 陈怡, 李国辉, 等. 急性髓系白血病患者 HtrA2 基因、 Set 基因表达与疗效和预后的关系研究. 现代生物医学进展, 2021, 21(11): 2077-2080.
46. 卞乐, 艾丽梅. 凋亡调节蛋白 XIAP 与 Omi/HtrA2 在弥漫大 B 细胞淋巴瘤中的表达及其与患者预后的关系. 临床荟萃, 2020, 35(5): 438-444.
47. Chen Q, Qu S, Liang Z, et al. Cathepsin H knockdown reverses radioresistance of hepatocellular carcinoma via metabolic switch followed by apoptosis. Int J Mol Sci, 2023, 24(6): 5257.
48. Zhang L, Li Y, Li X, et al. Regulation of HtrA2 on WT1 gene expression under imatinib stimulation and its effects on the cell biology of K562 cells. Oncol Lett, 2017, 14(3): 3862-3868.
49. Cilenti L, Kyriazis GA, Soundarapandian MM, et al. Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. Am J Physiol Renal Physiol, 2005, 288(2): F371-379.
50. Soyama H, Miyamoto M, Takano M, et al. Ovarian serous carcinomas acquire cisplatin resistance and increased invasion through downregulation of the high-temperature-required protein A2 (HtrA2), following repeated treatment with cisplatin. Med Oncol, 2017, 34(12): 201.
51. Mahbub AA, Le Maitre CL, Cross NA, et al. The effect of apigenin and chemotherapy combination treatments on apoptosis-related genes and proteins in acute leukaemia cell lines. Sci Rep, 2022, 12(1): 8858.

West China Medical Journal

Research progress of HtrA serine peptidase 2 in malignant tumors

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