Understanding The Regulatory Role of USP32 and SHMT2 in The Progression of Gastric Cancer

Document Type : Original Article

Authors

1 Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

2 Department of Emergency, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

3 Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China, 750001

Abstract

Objective: Gastric cancer is the fifth most common neoplasm and the fourth reason for mortality globally. Incidence
rates are highly variable and dependent on risk factors, epidemiologic and carcinogenesis patterns. Previous studies
reported that Helicobacter pylori (H. pylori) infection is one the strongest known risk factor for gastric cancer. USP32 is
a deubiquitinating enzyme identified as a potential factor associated with tumor progression and a key player in cancer
development. On the other hand, SHMT2 is involved in serine-glycine metabolism to support cancer cell proliferation.
Both USP32 and SHMT2 are reported to be upregulated in many cancer types, including gastric cancer, but its complete
mechanism is not fully explored yet. The present study explored possible mechanism of action of USP32 and SHMT2
in the progression of gastric cancer.
Materials and Methods: In this experimental study, Capsaicin (0.3 g/kg/day) and H. pylori infection combination was
used to successfully initiate gastric cancer conditions in mice. It was followed by 40 and 70 days of treatment to
establish initial and advanced conditions of gastric cancer.
Results: Histopathology confirmed formation of signet ring cell and initiation of cellular proliferation in the initial gastric
cancer. More proliferative cells were also observed. In addition, tissue hardening was confirmed in the advanced
stage of gastric cancer. USP32 and SHMT2 showed progressive upregulated expression, as gastric cancer progress.
Immunohistologically, it showed signals in abnormal cells and high-intensity signals in the advanced stage of cancer.
In USP32 silenced tissue, expression of SHMT2 was completely blocked and reverted cancer development as evident
with less abnormal cell in initial gastric cancer. Reduction of SHMT2 level to one-fourth was observed in the advanced
gastric cancer stages of USP32 silenced tissue.
Conclusion: USP32 had a direct role in regulating SHMT2 expression, which attracted therapeutic target for future
treatment.

Keywords

References

  1. Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol. 2019; 5(12): 1749-1768.
  2. Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol. 2020; 18(3): 534-542.
  3. Qinghai Z, Yanying W, Yunfang C, Xukui Z, Xiaoqiao Z. Effect of interleukin-17A and interleukin-17F gene polymorphisms on the risk of gastric cancer in a Chinese population. Gene. 2014; 537(2): 328-332.
  4. Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, et al. Association between IL-17A, -17F and MIF polymorphisms predispose to CpG island hyper-methylation in gastric cancer. Int J Mol Med. 2010; 25(3): 471-477.
  5. Lee H, Kim WJ, Kang HG, Jang JH, Choi IJ, Chun KH, et al. Upregulation of LAMB1 via ERK/c-Jun axis promotes gastric cancer growth and motility. Int J Mol Sci. 2021; 22(2): 626.
  6. Aksentijevich I, Zhou Q. NF-κB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol. 2017; 8: 399.
  7. Chen S, Chen X, Li Z, Mao J, Jiang W, Zhu Z, et al. Identification of ubiquitin-specific protease 32 as an oncogene in glioblastoma and the underlying mechanisms. Sci Rep. 2022; 12(1): 6445.
  8. Chandrasekaran AP, Kaushal K, Park CH, Kim KS, Ramakrishna S. USP32 confers cancer cell resistance to YM155 via promoting ER-associated degradation of solute carrier protein SLC35F2. Theranostics. 2021; 11(20): 9752-9771.
  9. Hu W, Wei H, Li K, Li P, Lin J, Feng R. Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer. Cell Prolif. 2017; 50(4): e12343.
  10. Dou N, Hu Q, Li L, Wu Q, Li Y, Gao Y. USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2. Int J Biol Sci. 2020; 16(9): 1648-1657.
  11. Wang Q, Tian J, Li X, Liu X, Zheng T, Zhao Y, et al. Upregulation of endothelial DKK1 (Dickkopf 1) promotes the development of pulmonary hypertension through the Sp1 (Specificity Protein 1)/ SHMT2 (Serine Hydroxymethyltransferase 2) pathway. Hypertension. 2022; 79(5): 960-973.
  12. Maddocks OD, Labuschagne CF, Adams PD, Vousden KH. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol Cell. 2016; 61(2): 210-221.
  13. Xie SY, Shi DB, Ouyang Y, Lin F, Chen XY, Jiang TC, et al. SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer. Am J Cancer Res. 2022; 12(7): 3405-3421.
  14. Shi H, Fang X, Li Y, Zhang Y. High expression of serine Hydroxymethyltransferase 2 indicates poor prognosis of gastric cancer patients. Med Sci Monit. 2019; 25: 7430-7438.
  15. Morscher RJ, Ducker GS, Li SH, Mayer JA, Gitai Z, Sperl W, et al. Mitochondrial translation requires folate-dependent tRNA methylation. Nature. 2018; 554(7690): 128-132.
  16. Ye J, Fan J, Venneti S, Wan YW, Pawel BR, Zhang J, et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 2014; 4(12): 1406-1417.
  17. Kottakis F, Nicolay BN, Roumane A, Karnik R, Gu H, Nagle JM, et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature. 2016; 539(7629): 390-395.
  18. Liu Y, Yin C, Deng MM, Wang Q, He XQ, Li MT, et al. High expression of SHMT2 is correlated with tumor progression and predicts poor prognosis in gastrointestinal tumors. Eur Rev Med Pharmacol Sci. 2019; 23(21): 9379-9392.
  19. Aziz F, Xin M, Gao Y, Chakroborty A, Khan I, Monts J, et al. Induction and prevention of gastric cancer with combined helicobacter pylori and capsaicin administration and DFMO treatment, respectively. Cancers (Basel). 2020; 12(4): 816.
  20. Pernot S, Voron T, Perkins G, Lagorce-Pages C, Berger A, TaiebJ. Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol. 2015; 21(40): 11428-11438.
  21. Zavros Y. Initiation and maintenance of gastric cancer: a focus on CD44 variant isoforms and cancer stem cells. Cell Mol Gastroenterol Hepatol. 2017; 4(1): 55-63.
  22. Ebata T, Mitsui Y, Sugimoto W, Maeda M, Araki K, Machiyama H, et al. Substrate stiffness influences doxorubicin-induced p53 activation via ROCK2 expression. Biomed Res Int. 2017; 2017: 5158961.
  23. Cai J, Li M, Wang X, Li L, Li Q, Hou Z, et al. USP37 promotes lung cancer cell migration by stabilizing snail protein via deubiquitination. Front Genet. 2020; 10: 1324.
  24. Qin T, Li B, Feng X, Fan S, Liu L, Liu D, et al. Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity. J Exp Clin Cancer Res. 2018; 37(1): 287.
  25. Anderson DD, Stover PJ. SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS One. 2009; 4(6): e5839.
  26. Kim D, Fiske BP, Birsoy K, Freinkman E, Kami K, Possemato RL, et al. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature. 2015; 520(7547): 363-367.
Cell Journal (Yakhteh)
Volume 25, Issue 4
April 2023
Pages 222-228

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