Clinical significance of HIBADH protein in gastric adenocarcinoma tissues and its function in gastric cancer cells_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Jugang , PEI Guoqing , YANG Jianjun , HUO Haizhong , SONG Zhicheng , YU Jiwei ,  GU Yan

Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P. R. China;

Corresponding author：

GU Yan, Email: yangu@sjtu.edu.cn

Keywords：

3-hydroxyisobutyrate dehydrogenase; gastric cancer; prognosis; cell movement

DOI：

10.7507/1007-9424.201810026

Video：

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Objective To study the clinical significance of the 3-hydroxyisobutyrate dehydrogenase (HIBADH) expressions in gastric adenocarcinoma tissues and its biological function in gastric cancer cells.Methods Seventy-six patients with gastric adenocarcinoma who were hospitalized in Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiaotong University, School of Medicine between January 2006 and December 2007 were recruited in our research. Immunohistochemical (IHC) staining was used to detect the HIBADH protein in primary gastric adenocarcinoma tissues, adjacent tissues, and metastatic lymph node tissues of gastric cancer. Then, the relationships among the expression of HIBADH protein, the clinical features, and the prognosis were analyzed. The MKN45 gastric cancer cell line of HIBADH overexpression was picked up and constructed as stable HIBADH knockdown cell lines. The biological function of HIBADH protein in gastric cancer cells was confirmed through in vitro experiments such as cell proliferation assay, migration and invasion assay, and scratch-wound assay.Results The positive expression rate of HIBADH protein in the 76 gastric adenocarcinoma tissues was significantly higher than that of the adjacent tissues (χ²=54.738, P<0.001). Moreover, the higher expression level of HIBADH protein was related to the larger tumor diameter, the higher tumor lymphatic invasion rate, the later pT stage, the higher the lymph node metastasis rate, and the later pTNM stage (P<0.05). HIBADH protein was also highly expressed in lymph nodes with metastatic carcinoma, and positiverate was 100% (48/48). The 10-year survival rate of patients in the HIBADH protein positive group and HIBADH protein negative group were 16.4% and 69.4%, respectively, which showed the latter group had a longer survival time (χ²=19.612, P<0.001). The migration capacity, invasion capacity, and scratch-wound capacity of the MKN45 cells were significantly decreased after HIBADH protein knockdown (P<0.05), but the proliferation capacity of the cells was not significantly changed (P>0.05).Conclusions The overexpression of HIBADH protein in gastric cancer suggests later tumor stage and poor prognosis. Inhibition expression of HIBADH protein can reduce the motility capacity of gastric cancer cells.

Citation： WU Jugang, PEI Guoqing, YANG Jianjun, HUO Haizhong, SONG Zhicheng, YU Jiwei, GU Yan. Clinical significance of HIBADH protein in gastric adenocarcinoma tissues and its function in gastric cancer cells. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(3): 294-300. doi: 10.7507/1007-9424.201810026 Copy

1.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2.	Matsuoka T, Yashiro M. Biomarkers of gastric cancer: current topics and future perspective. World J Gastroenterol, 2018, 24(26): 2818-2832.
3.	Magalhães H, Fontes-Sousa M, Machado M. Immunotherapy in advanced gastric cancer: an overview of the emerging strategies. Can J Gastroenterol Hepatol, 2018, 2018: 2732408.
4.	Chao HC, Chung CL, Pan HA, et al. Protein tyrosine phosphatase non-receptor type 14 is a novel sperm-motility biomarker. J Assist Reprod Genet, 2011, 28(9): 851-861.
5.	Rougraff PM, Paxton R, Kuntz MJ, et al. Purification and characterization of 3-hydroxyisobutyrate dehydrogenase from rabbit liver. J Biol Chem, 1988, 263(1): 327-331.
6.	Rougraff PM, Zhang B, Kuntz MJ, et al. Cloning and sequence analysis of a cDNA for 3-hydroxyisobutyrate dehydrogenase. J Biol Chem, 1989, 264(10): 5899-5903.
7.	Zhao C, Huo R, Wang FQ, et al. Identification of several proteins involved in regulation of sperm motility by proteomic analysis. Fertil Steril, 2007, 87(2): 436-438.
8.	Martínez-Heredia J, de Mateo S, Vidal-Taboada JM, et al. Identification of proteomic differences in asthenozoospermic sperm samples. Hum Reprod, 2008, 23(4): 783-791.
9.	Yue Q, Zhen H, Huang M, et al. Proteasome inhibition contributed to the cytotoxicity of arenobufagin after its binding with Na,K-ATPase in human cervical carcinoma HeLa cells. PLoS One, 2016, 11(7): e0159034.
10.	Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2016, 27(suppl 5): v38-v49.
11.	Chen DH, Yu JW, Wu JG, et al. Significances of contactin-1 expression in human gastric cancer and knockdown of contactin-1 expression inhibits invasion and metastasis of MKN45 gastric cancer cells. J Cancer Res Clin Oncol, 2015, 141(12): 2109-2120.
12.	Du Y, Jiang B, Song S, et al. Metadherin regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition. Int J Oncol, 2017, 51(1): 63-74.
13.	Song S, Pei G, Du Y, et al. Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells. Am J Transl Res, 2018, 10(1): 304-314.
14.	Pei G, Luo M, Ni X, et al. Autophagy facilitates metadherin-induced chemotherapy resistance through the AMPK/ATG5 pathway in gastric cancer. Cell Physiol Biochem, 2018, 46(2): 847-859.
15.	Njau RK, Herndon CA, Hawes JW. New developments in our understanding of the beta-hydroxyacid dehydrogenases. Chem Biol Interact, 2001, 130-132(1-3): 785-791.
16.	Li L, Dworkowski FS, Cook PF. Importance in catalysis of the6-phosphate-binding site of 6-phosphogluconate in sheep liver6-phosphogluconate dehydrogenase. J Biol Chem, 2006, 281(35): 25568-25576.
17.	Chen YY, Ko TP, Chen WH, et al. Conformational changes associated with cofactor/substrate binding of 6-phosphogluconate dehydrogenase from Escherichia coli and Klebsiella pneumoniae: implications for enzyme mechanism. J Struct Biol, 2010, 169(1): 25-35.
18.	Reitz S, Alhapel A, Essen LO, et al. Structural and kinetic properties of a beta-hydroxyacid dehydrogenase involved in nicotinate fermentation. J Mol Biol, 2008, 382(3): 802-811.
19.	Tchigvintsev A, Singer A, Brown G, et al. Biochemical and structural studies of uncharacterized protein PA0743 from Pseudomonas aeruginosa revealed NAD+-dependent L-serine dehydrogenase. J Biol Chem, 2012, 287(3): 1874-1883.
20.	Zhang Y, Zheng Y, Qin L, et al. Structural characterization of aβ-hydroxyacid dehydrogenase from Geobacter sulfurreducens and Geobacter metallireducens with succinic semialdehyde reductase activity. Biochimie, 2014, 104: 61-69.
21.	Murín R, Schaer A, Kowtharapu BS, et al. Expression of3-hydroxyisobutyrate dehydrogenase in cultured neural cells. J Neurochem, 2008, 105(4): 1176-1186.
22.	Tasi YC, Chao HC, Chung CL, et al. Characterization of3-hydroxyisobutyrate dehydrogenase, HIBADH, as a sperm-motility marker. J Assist Reprod Genet, 2013, 30(4): 505-512.
23.	Ishak Gabra MB, Yang Y, Lowman XH, et al. IKKβ activates p53 to promote cancer cell adaptation to glutamine deprivation. Oncogenesis, 2018, 7(11): 93.
24.	Jiang Z, Zhang C, Gan L, et al. iTRAQ based quantitative proteomics approach identifies novel diagnostic biomarkers that were essential for glutamine metabolism and redox homeostasis for gastric cancer. Proteomics Clin Appl, 2018, [Epub ahead of print].
25.	Xiao S, Zhou L. Gastric cancer: metabolic and metabolomics perspectives (review). Int J Oncol, 2017, 51(1): 5-17.

1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: current topics and future perspective. World J Gastroenterol, 2018, 24(26): 2818-2832.
3. Magalhães H, Fontes-Sousa M, Machado M. Immunotherapy in advanced gastric cancer: an overview of the emerging strategies. Can J Gastroenterol Hepatol, 2018, 2018: 2732408.
4. Chao HC, Chung CL, Pan HA, et al. Protein tyrosine phosphatase non-receptor type 14 is a novel sperm-motility biomarker. J Assist Reprod Genet, 2011, 28(9): 851-861.
5. Rougraff PM, Paxton R, Kuntz MJ, et al. Purification and characterization of 3-hydroxyisobutyrate dehydrogenase from rabbit liver. J Biol Chem, 1988, 263(1): 327-331.
6. Rougraff PM, Zhang B, Kuntz MJ, et al. Cloning and sequence analysis of a cDNA for 3-hydroxyisobutyrate dehydrogenase. J Biol Chem, 1989, 264(10): 5899-5903.
7. Zhao C, Huo R, Wang FQ, et al. Identification of several proteins involved in regulation of sperm motility by proteomic analysis. Fertil Steril, 2007, 87(2): 436-438.
8. Martínez-Heredia J, de Mateo S, Vidal-Taboada JM, et al. Identification of proteomic differences in asthenozoospermic sperm samples. Hum Reprod, 2008, 23(4): 783-791.
9. Yue Q, Zhen H, Huang M, et al. Proteasome inhibition contributed to the cytotoxicity of arenobufagin after its binding with Na,K-ATPase in human cervical carcinoma HeLa cells. PLoS One, 2016, 11(7): e0159034.
10. Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2016, 27(suppl 5): v38-v49.
11. Chen DH, Yu JW, Wu JG, et al. Significances of contactin-1 expression in human gastric cancer and knockdown of contactin-1 expression inhibits invasion and metastasis of MKN45 gastric cancer cells. J Cancer Res Clin Oncol, 2015, 141(12): 2109-2120.
12. Du Y, Jiang B, Song S, et al. Metadherin regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition. Int J Oncol, 2017, 51(1): 63-74.
13. Song S, Pei G, Du Y, et al. Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells. Am J Transl Res, 2018, 10(1): 304-314.
14. Pei G, Luo M, Ni X, et al. Autophagy facilitates metadherin-induced chemotherapy resistance through the AMPK/ATG5 pathway in gastric cancer. Cell Physiol Biochem, 2018, 46(2): 847-859.
15. Njau RK, Herndon CA, Hawes JW. New developments in our understanding of the beta-hydroxyacid dehydrogenases. Chem Biol Interact, 2001, 130-132(1-3): 785-791.
16. Li L, Dworkowski FS, Cook PF. Importance in catalysis of the6-phosphate-binding site of 6-phosphogluconate in sheep liver6-phosphogluconate dehydrogenase. J Biol Chem, 2006, 281(35): 25568-25576.
17. Chen YY, Ko TP, Chen WH, et al. Conformational changes associated with cofactor/substrate binding of 6-phosphogluconate dehydrogenase from Escherichia coli and Klebsiella pneumoniae: implications for enzyme mechanism. J Struct Biol, 2010, 169(1): 25-35.
18. Reitz S, Alhapel A, Essen LO, et al. Structural and kinetic properties of a beta-hydroxyacid dehydrogenase involved in nicotinate fermentation. J Mol Biol, 2008, 382(3): 802-811.
19. Tchigvintsev A, Singer A, Brown G, et al. Biochemical and structural studies of uncharacterized protein PA0743 from Pseudomonas aeruginosa revealed NAD+-dependent L-serine dehydrogenase. J Biol Chem, 2012, 287(3): 1874-1883.
20. Zhang Y, Zheng Y, Qin L, et al. Structural characterization of aβ-hydroxyacid dehydrogenase from Geobacter sulfurreducens and Geobacter metallireducens with succinic semialdehyde reductase activity. Biochimie, 2014, 104: 61-69.
21. Murín R, Schaer A, Kowtharapu BS, et al. Expression of3-hydroxyisobutyrate dehydrogenase in cultured neural cells. J Neurochem, 2008, 105(4): 1176-1186.
22. Tasi YC, Chao HC, Chung CL, et al. Characterization of3-hydroxyisobutyrate dehydrogenase, HIBADH, as a sperm-motility marker. J Assist Reprod Genet, 2013, 30(4): 505-512.
23. Ishak Gabra MB, Yang Y, Lowman XH, et al. IKKβ activates p53 to promote cancer cell adaptation to glutamine deprivation. Oncogenesis, 2018, 7(11): 93.
24. Jiang Z, Zhang C, Gan L, et al. iTRAQ based quantitative proteomics approach identifies novel diagnostic biomarkers that were essential for glutamine metabolism and redox homeostasis for gastric cancer. Proteomics Clin Appl, 2018, [Epub ahead of print].
25. Xiao S, Zhou L. Gastric cancer: metabolic and metabolomics perspectives (review). Int J Oncol, 2017, 51(1): 5-17.

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Clinical significance of HIBADH protein in gastric adenocarcinoma tissues and its function in gastric cancer cells

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