Research Article
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The Importance of Adropin and Hypoxia Inducible Factor-1 Alpha in Gastric Cancer

Year 2024, Volume: 15 Issue: 3, 369 - 375, 30.09.2024
https://doi.org/10.18663/tjcl.1442369

Abstract

Aim: Gastric cancer accounts for 5.6% of all new cancer cases worldwide and is the fifth most common type of cancer. It ranks third in cancer-related mortality. With the current standard neoadjuvant treatment of localised gastric cancer, appropriate resection can be performed in approximately 75% of patients. While the two-year survival rate of patients is approximately 70 %, this rate decreases to 45 % in the fifth year. Although high curative treatment rates and long-term survival success are achieved with early diagnosis in many cancer types, unfortunately the same is not the case for gastric cancer and the unmet need for treatment continues.
Adropin is a peptide secreted from many tissues in our body and has a regulatory role in energy homeostasis, angiogenesis, cell proliferation and cell migration processes. Hypoxia-inducible factor (HIF) is activated when oxygen levels decrease in tissues and regulates the growth, development, and differentiation of cells.
A prospective study was planned to investigate the role of adropin and HIF-1α on the pathogenesis of gastric cancer and the relation of treatment response rates with adropin and HIF-1α levels by comparing adropin and HIF-1α levels in newly diagnosed locally advanced gastric cancer patients with adropin and HIF-1α levels in healthy individuals.
Material and Methods: Adropin and HIF-1α levels were compared between newly diagnosed patients with localised gastric cancer receiving neoadjuvant chemotherapy and healthy control group. We also examined whether there was a correlation between clinical and pathological response rates and adropin and HIF-1α levels in patients who completed the treatment.
Results: Adropin levels were statistically significantly lower and HIF-1α levels were statistically significantly higher in patients with gastric cancer. No significant difference was observed between adropin and HIF-1α levels and various clinical variables such as clinical response, pathological response, operability status, new pathological T (ypT) and new pathological N (ypN) stages..
Conclusion: It was important to demonstrate the relationship between adropin and gastric cancer, which had not been previously investigated and for which no data were identified through a literature review. It is obvious that adropin and HIF-1α are two important factors involved in gastric cancer. In addition adropin and HIF-1α may be two important parameters for early diagnosis of gastric cancer. Further studies are needed to elucidate the role of adropin and HIF-1α in gastric cancer.

References

  • Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249.
  • Machlowska J, et al. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci. 2020 Jun 4;21(11):4012.
  • Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol. 2016 Feb 28;22(8):2403-14.
  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Gastric Cancer Version 2.2023 — August 29, 2023
  • Cunningham D, et al. MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.
  • Al-Batran SE, et al. FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957.
  • Kumar KG, et al. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
  • Lovren F, et al. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
  • Jia L, et al. Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression. BMC Cancer. 2023 Oct 30;23(1):1042. doi: 10.1186/s12885-023-11519-5. Erratum in: BMC Cancer. 2023 Nov 10;23(1):1094.
  • Stelcer E, et al. Adropin Stimulates Proliferation and Inhibits Adrenocortical Steroidogenesis in the Human Adrenal Carcinoma (HAC15) Cell Line. Front Endocrinol (Lausanne). 2020 Oct 8;11:561370.
  • Nergiz S, et al. Circulating adropin levels in patients with endometrium cancer. Gynecol Endocrinol. 2015;31(9):730-5.
  • Hu J, et al. High Level of Adropin Promotes the Progression of Pancreatic Ductal Adenocarcinoma. Curr Cancer Drug Targets. 2023 Nov 21.
  • Rao A, Herr DR. G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. Biochim Biophys Acta Mol Cell Res. 2017 Jul;1864(7):1318-1327.
  • Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001 Jun;11(3):293-9.
  • Wang, Guang L., et al. "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension." Proceedings of the national academy of sciences 92.12 (1995): 5510-5514.
  • Maxwell, Patrick H., et al. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis." Nature 399.6733 (1999): 271-275.
  • Bao MH, Wong CC. Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells. 2021 Jul 6;10(7):1715.
  • Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020 Oct 1;130(10):5074-5087.
  • Semenza GL. Intratumoral Hypoxia and Mechanisms of Immune Evasion Mediated by Hypoxia-Inducible Factors. Physiology (Bethesda). 2021 Mar 1;36(2):73-83.
  • Zang H, et al. Serum adropin levels are decreased in Chinese type 2 diabetic patients and negatively correlated with body mass index. Endocr J. 2018 Jul 28;65(7):685-691.
  • Infantino V, et al. Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int J Mol Sci. 2021 May 27;22(11):5703.
  • Piao HY, et al. Hypoxia associated lncRNA HYPAL promotes proliferation of gastric cancer as ceRNA by sponging miR-431-5p to upregulate CDK14. Gastric Cancer. 2022 Jan;25(1):44-63.
  • Liu L, et al. ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer. Int J Cancer. 2010 Aug 15;127(4):820-9.
  • Okazaki M, et al. The effect of HIF-1α and PKM1 expression on acquisition of chemoresistance. Cancer Manag Res. 2018 Jul 4;10:1865-1874.
  • Li Z, et al. Natriuretic peptide receptor a promotes gastric malignancy through angiogenesis process. Cell Death Dis. 2021 Oct 20;12(11):968.
  • Wu T, et al. EDDM3A drives gastric cancer progression by promoting HIF-1α-dependent aerobic glycolysis. Oncogenesis. 2022 Jan 17;11(1):3.
  • Shirai Y, et al. An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor. Cancers (Basel). 2021 Jun 4;13(11):2813.
  • Al-Batran SE, et al. FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957.

Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi

Year 2024, Volume: 15 Issue: 3, 369 - 375, 30.09.2024
https://doi.org/10.18663/tjcl.1442369

Abstract

Amaç: Mide kanseri tüm dünyada ki yeni kanser vakalarının %5,6’sını oluşturur ve beşinci en sık görülen kanser türüdür. Kansere bağlı ölüm sıralamasında ise üçüncü sırada yer almaktadır. Lokalileri mide kanserinde, günümüzde ki standart neoadjuvan tedavi ile hastaların yalaşık % 75’ine uygun rezeksiyon yapılabilmektedir. Hastaların iki yıllık hayatta kalma oranları yaklaşık %70 iken bu oran beşinci yılda %45’lere düşmektedir. Bir çok kanser türünde erken tanı ile yüksek küratif tedavi oranları ve uzun süreli sağkalım başarısı sağlanmasına rağmen mide kanseri için malesef aynı durum sözkonusu değildir ve karşılanmamış tedavi ihtiyacı devam etmektedir.
Adropin, vücudumuzda birçok dokudan salgılanan; başlıca enerji homeostazisi, anjiyogenez, hücre proliferasyonu ve hücre göçü süreçlerinde düzenleyici rolü olan bir peptittir. Hipoksi ile indükenebilir faktör (HIF) ise dokularda oksijen seviyeleri düşünce aktive olur ve hücrelerin büyümesi, gelişmesi ve farklılaşmasını regüle eder.
Yeni tanı almış lokal ileri mide kanseri hastalarında ki adropin ve HIF-1α sevyeleri ile sağlıklı bireylerdeki adropin ve HIF1-α seviyeleri karşılaştırılarak, adropinin ve HIF1-α’nın mide kanseri patogenezi üzerinde rolü ve tedavi yanıt oranlarının adropin ve HIF-1α seviyeleri ile ilişkisinin araştırılması amacıyla prosektif bir çalışma planlandı.
Gereç ve Yöntemler: Yeni tanı almış, neoadjuvan kemoterapi alacak olan lokalileri mide kanserli hastalar ve sağlıklı kontrol grubu arasında adropin ve HIF-1α düzeyleri karşılaştırıldı. Ayrıca tedaviyi tamamlayan hastalarda klinik ve patolojik yanıt oranları ile adropin ve HIF-1α düzeyleri arasında bir ilişki olup olmadığına bakıldı.
Bulgular: Adropin, mide kanserli hastalarda istatistiksel anlamlı olarak daha düşük, HIF-1α düzeyleri ise mide kanserli hastalarda istatistiksel anlamlı olarak daha yüksek bulundu. Adropin ve HIF-1α düzeyleri ile klinik yanıt, patolojik yanıt, operabilite durumu, yeni patolojik T (ypT) ve yeni patolojik N (ypN) evreleri gibi çeşitli klinik değişkenler arasında anlamlı bir farklılık görülmedi.
Sonuç: Daha önce araştırılmamış olan ve literatür taraması yoluyla herhangi bir veri tespit edilemeyen adropin ve mide kanseri arasındaki ilişkiyi ortaya koymak önemliydi. Adropin ve HIF-1α'nın mide kanserinde rol oynayan iki önemli faktör olduğu açıktır. Ayrıca adropin ve HIF-1α mide kanserinin erken teşhisi için iki önemli parametre olabilir. Adropin ve HIF-1α'nın mide kanserindeki rolünü aydınlatmak için daha fazla çalışmaya ihtiyaç vardır.

Ethical Statement

ATATÜRK ÜNİVERSİTESİ ETİK KURULUNDAN ONAY ALINMIŞTIR.

References

  • Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249.
  • Machlowska J, et al. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci. 2020 Jun 4;21(11):4012.
  • Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol. 2016 Feb 28;22(8):2403-14.
  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Gastric Cancer Version 2.2023 — August 29, 2023
  • Cunningham D, et al. MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.
  • Al-Batran SE, et al. FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957.
  • Kumar KG, et al. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
  • Lovren F, et al. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
  • Jia L, et al. Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression. BMC Cancer. 2023 Oct 30;23(1):1042. doi: 10.1186/s12885-023-11519-5. Erratum in: BMC Cancer. 2023 Nov 10;23(1):1094.
  • Stelcer E, et al. Adropin Stimulates Proliferation and Inhibits Adrenocortical Steroidogenesis in the Human Adrenal Carcinoma (HAC15) Cell Line. Front Endocrinol (Lausanne). 2020 Oct 8;11:561370.
  • Nergiz S, et al. Circulating adropin levels in patients with endometrium cancer. Gynecol Endocrinol. 2015;31(9):730-5.
  • Hu J, et al. High Level of Adropin Promotes the Progression of Pancreatic Ductal Adenocarcinoma. Curr Cancer Drug Targets. 2023 Nov 21.
  • Rao A, Herr DR. G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. Biochim Biophys Acta Mol Cell Res. 2017 Jul;1864(7):1318-1327.
  • Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001 Jun;11(3):293-9.
  • Wang, Guang L., et al. "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension." Proceedings of the national academy of sciences 92.12 (1995): 5510-5514.
  • Maxwell, Patrick H., et al. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis." Nature 399.6733 (1999): 271-275.
  • Bao MH, Wong CC. Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells. 2021 Jul 6;10(7):1715.
  • Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020 Oct 1;130(10):5074-5087.
  • Semenza GL. Intratumoral Hypoxia and Mechanisms of Immune Evasion Mediated by Hypoxia-Inducible Factors. Physiology (Bethesda). 2021 Mar 1;36(2):73-83.
  • Zang H, et al. Serum adropin levels are decreased in Chinese type 2 diabetic patients and negatively correlated with body mass index. Endocr J. 2018 Jul 28;65(7):685-691.
  • Infantino V, et al. Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int J Mol Sci. 2021 May 27;22(11):5703.
  • Piao HY, et al. Hypoxia associated lncRNA HYPAL promotes proliferation of gastric cancer as ceRNA by sponging miR-431-5p to upregulate CDK14. Gastric Cancer. 2022 Jan;25(1):44-63.
  • Liu L, et al. ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer. Int J Cancer. 2010 Aug 15;127(4):820-9.
  • Okazaki M, et al. The effect of HIF-1α and PKM1 expression on acquisition of chemoresistance. Cancer Manag Res. 2018 Jul 4;10:1865-1874.
  • Li Z, et al. Natriuretic peptide receptor a promotes gastric malignancy through angiogenesis process. Cell Death Dis. 2021 Oct 20;12(11):968.
  • Wu T, et al. EDDM3A drives gastric cancer progression by promoting HIF-1α-dependent aerobic glycolysis. Oncogenesis. 2022 Jan 17;11(1):3.
  • Shirai Y, et al. An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor. Cancers (Basel). 2021 Jun 4;13(11):2813.
  • Al-Batran SE, et al. FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957.
There are 28 citations in total.

Details

Primary Language Turkish
Subjects Clinical Oncology, Predictive and Prognostic Markers, Medical Biochemistry - Proteins, Peptides and Proteomics
Journal Section Research Article
Authors

Alperen Akansel Çağlar 0000-0001-8541-3418

Zekeriya Hannarici 0000-0002-6547-0199

Mehmet Emin Büyükbayram 0000-0002-5454-7576

Aykut Turhan 0000-0002-2535-9816

Pınar Çoban Eşdur 0000-0002-4487-9139

Esra Eğilmez 0000-0003-2706-7101

Çağrı Kızıltunç 0000-0001-7455-8136

Mehmet Bilici 0000-0003-1306-2238

Salim Başol Tekin 0000-0002-0974-3412

Publication Date September 30, 2024
Submission Date February 26, 2024
Acceptance Date July 22, 2024
Published in Issue Year 2024 Volume: 15 Issue: 3

Cite

APA Çağlar, A. A., Hannarici, Z., Büyükbayram, M. E., Turhan, A., et al. (2024). Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi. Turkish Journal of Clinics and Laboratory, 15(3), 369-375. https://doi.org/10.18663/tjcl.1442369
AMA Çağlar AA, Hannarici Z, Büyükbayram ME, Turhan A, Çoban Eşdur P, Eğilmez E, Kızıltunç Ç, Bilici M, Tekin SB. Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi. TJCL. September 2024;15(3):369-375. doi:10.18663/tjcl.1442369
Chicago Çağlar, Alperen Akansel, Zekeriya Hannarici, Mehmet Emin Büyükbayram, Aykut Turhan, Pınar Çoban Eşdur, Esra Eğilmez, Çağrı Kızıltunç, Mehmet Bilici, and Salim Başol Tekin. “Mide Kanserinde Adropin Ve Hipoksi Ile indüklenebilir faktör -1 alfa’nın önemi”. Turkish Journal of Clinics and Laboratory 15, no. 3 (September 2024): 369-75. https://doi.org/10.18663/tjcl.1442369.
EndNote Çağlar AA, Hannarici Z, Büyükbayram ME, Turhan A, Çoban Eşdur P, Eğilmez E, Kızıltunç Ç, Bilici M, Tekin SB (September 1, 2024) Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi. Turkish Journal of Clinics and Laboratory 15 3 369–375.
IEEE A. A. Çağlar, “Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi”, TJCL, vol. 15, no. 3, pp. 369–375, 2024, doi: 10.18663/tjcl.1442369.
ISNAD Çağlar, Alperen Akansel et al. “Mide Kanserinde Adropin Ve Hipoksi Ile indüklenebilir faktör -1 alfa’nın önemi”. Turkish Journal of Clinics and Laboratory 15/3 (September 2024), 369-375. https://doi.org/10.18663/tjcl.1442369.
JAMA Çağlar AA, Hannarici Z, Büyükbayram ME, Turhan A, Çoban Eşdur P, Eğilmez E, Kızıltunç Ç, Bilici M, Tekin SB. Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi. TJCL. 2024;15:369–375.
MLA Çağlar, Alperen Akansel et al. “Mide Kanserinde Adropin Ve Hipoksi Ile indüklenebilir faktör -1 alfa’nın önemi”. Turkish Journal of Clinics and Laboratory, vol. 15, no. 3, 2024, pp. 369-75, doi:10.18663/tjcl.1442369.
Vancouver Çağlar AA, Hannarici Z, Büyükbayram ME, Turhan A, Çoban Eşdur P, Eğilmez E, Kızıltunç Ç, Bilici M, Tekin SB. Mide kanserinde adropin ve hipoksi ile indüklenebilir faktör -1 alfa’nın önemi. TJCL. 2024;15(3):369-75.


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