Importance of β-Catenin and DRP-1 Expression in Hepatocellular Carcinomas
Yıl 2025,
Cilt: 8 Sayı: 5, 197 - 201, 15.09.2025
Sevilay Özmen
,
Elif Demirci
,
Rabia Demirtaş
,
Onur Ceylan
,
Keziban Ülke Esin
,
Salih Kara
,
Nurhak Aksungur
,
Necip Altundaş
,
Fatih Alper
,
Hakan Dursun
,
Gürkan Öztürk
,
İbrahim Karabulut
,
Rabia Selen
Öz
Hepatocellular carcinoma (HCC) represents one of the most prevalent primary liver malignancies. The activation of the Wnt/β-catenin signaling pathway is frequently observed in HCC, contributing to tumor progression. Dynamin-related protein-1 (DRP-1) is involved in apoptosis, tumor metastasis, and suppression of cell adhesion and migration. While DRP-1 and β-catenin have been reported in various tumors, their significance in HCC remains controversial. This study investigates the immunohistochemical (IHC) expression of β-catenin and DRP-1 in HCC. Thirty HCC cases diagnosed within the last 15 years at our institution were included. IHC staining with β-catenin and DRP-1 antibodies was performed on paraffin-embedded tumor and non-tumor tissue samples. Thus, the expressions of these proteins were analyzed. Among 30 cases, 25 had a cirrhotic background, while 5 were non-cirrhotic. IHC analysis revealed membranous β-catenin reactivity in tumor areas in 29 cases, with one case exhibiting both membranous and nuclear reactivity. Weaker immunoreactivity was observed in non-tumoral hepatocytes and biliary epithelium compared to tumor areas. DRP-1 expression was absent in non-tumoral hepatocytes, while cytoplasmic immunoreactivity was statistically strong in 16 cases (53%) (P=0.0008). No correlation was found between nuclear grade, lymphovascular invasion, serum AFP levels, necrosis, survival, and β-catenin or DRP-1 expression (P>0.05). Our findings suggest a potential role for DRP-1 in HCC pathogenesis. While no significant correlation with prognostic parameters was observed in our limited cohort, further multicenter studies with larger, heterogeneous patient groups are warranted.
Etik Beyan
The study was approved by the Clinical Research Ethics Council of Ataturk University (approval date: June 18, 2023, protocol code: B.30.2.ATA.0.01.00/681).
Kaynakça
-
Bosman FT, Carneiro F, Hruban RH, Theise ND. 2010. WHO classification of tumours of the digestive system (4th ed). IARC Press, Lyon, France, pp: 45-85.
-
Di Tommaso L, Franchi G, Park YN. 2007. Diagnostic value of HSP70, Glypican 3, and Glutamine Synthetase in hepatocellular nodules in cirrhosis. Hepatology, 45(3): 725–734.
-
Durnez A, Verslype C, Nevens F. 2006. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma: A possible progenitor cell origin. Histopathology, 49(2): 138–151.
-
Eisner V, Picard M, Hajnóczky G. 2018. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol, 20(6): 755–765.
-
El-Serag HB, Rudolph KL. 2007. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology, 132(6):2557–2576.
-
Forner A, Vilana R, Ayuso C. 2008. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology, 47(1): 97–104.
-
Hu C, Huang Y, Li L. 2017. Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progress in mammals. Int J Mol Sci, 18(1): 144.
-
Lima AR, Santos L, Correia M. 2018. Dynamin-related protein 1 at the crossroads of cancer. Genes, 9(2): 115.
-
Ma M, Lin XH, Liu HH, Zhang R, Chen RX. 2020. Suppression of DRP1 mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy. Oncol Rep, 43(3): 1010–1018.
-
Nault JC, Calderaro J, Di Tommaso L, Balabaud C, Zafrani ES, Bioulac-Sage P, Roncalli M, Zucman-Rossi J. 2014. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology, 60(6): 1983–1992.
-
Qian W, Wang J, Van Houten B. 2013. The role of dynamin-related protein 1 in cancer growth: A promising therapeutic target? Expert Opin Ther Targets, 17(9): 997–1001.
-
Rehman J, Zhang HJ, Toth PT. 2012. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J, 26(6): 2175–2186.
-
Roskams T, Kojiro M. 2010. Pathology of early hepatocellular carcinoma: Conventional and molecular diagnosis. Semin Liver Dis, 30(1): 17–25.
-
Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S. 2015. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet, 47(5): 505–511.
-
Shen F, Gai J, Xing J. 2018. Dynasore suppresses proliferation and induces apoptosis of the non-small-cell lung cancer cell line A549. Biochem Biophys Res Commun, 495(1): 1158–1166.
-
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. 2019. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 16(10): 589–604.
-
Zhai J, Wang Y, Yang F, Hu J, Qi Q, Zhang Y. 2014. DRP-1, ezrin, and E-cadherin expression and their association with esophageal squamous cell carcinoma. Oncol Lett, 8(1): 133–138.
-
Zhao J, Zhang J, Yu M. 2013. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene, 32(40): 4814–4824.
-
Zhao T, Guo BJ, Xiao CL, Chen JJ, Lü C, Fang FF, Li B. 2021. Aerobic exercise suppresses hepatocellular carcinoma by downregulating dynamin-related protein 1 through the PI3K/AKT pathway. J Integr Med, 19(5): 418–427.
Importance of β-Catenin and DRP-1 Expression in Hepatocellular Carcinomas
Yıl 2025,
Cilt: 8 Sayı: 5, 197 - 201, 15.09.2025
Sevilay Özmen
,
Elif Demirci
,
Rabia Demirtaş
,
Onur Ceylan
,
Keziban Ülke Esin
,
Salih Kara
,
Nurhak Aksungur
,
Necip Altundaş
,
Fatih Alper
,
Hakan Dursun
,
Gürkan Öztürk
,
İbrahim Karabulut
,
Rabia Selen
Öz
Hepatocellular carcinoma (HCC) represents one of the most prevalent primary liver malignancies. The activation of the Wnt/β-catenin signaling pathway is frequently observed in HCC, contributing to tumor progression. Dynamin-related protein-1 (DRP-1) is involved in apoptosis, tumor metastasis, and suppression of cell adhesion and migration. While DRP-1 and β-catenin have been reported in various tumors, their significance in HCC remains controversial. This study investigates the immunohistochemical (IHC) expression of β-catenin and DRP-1 in HCC. Thirty HCC cases diagnosed within the last 15 years at our institution were included. IHC staining with β-catenin and DRP-1 antibodies was performed on paraffin-embedded tumor and non-tumor tissue samples. Thus, the expressions of these proteins were analyzed. Among 30 cases, 25 had a cirrhotic background, while 5 were non-cirrhotic. IHC analysis revealed membranous β-catenin reactivity in tumor areas in 29 cases, with one case exhibiting both membranous and nuclear reactivity. Weaker immunoreactivity was observed in non-tumoral hepatocytes and biliary epithelium compared to tumor areas. DRP-1 expression was absent in non-tumoral hepatocytes, while cytoplasmic immunoreactivity was statistically strong in 16 cases (53%) (P=0.0008). No correlation was found between nuclear grade, lymphovascular invasion, serum AFP levels, necrosis, survival, and β-catenin or DRP-1 expression (P>0.05). Our findings suggest a potential role for DRP-1 in HCC pathogenesis. While no significant correlation with prognostic parameters was observed in our limited cohort, further multicenter studies with larger, heterogeneous patient groups are warranted.
Etik Beyan
The study was approved by the Clinical Research Ethics Council of Ataturk University (approval date: June 18, 2023, protocol code: B.30.2.ATA.0.01.00/681).
Kaynakça
-
Bosman FT, Carneiro F, Hruban RH, Theise ND. 2010. WHO classification of tumours of the digestive system (4th ed). IARC Press, Lyon, France, pp: 45-85.
-
Di Tommaso L, Franchi G, Park YN. 2007. Diagnostic value of HSP70, Glypican 3, and Glutamine Synthetase in hepatocellular nodules in cirrhosis. Hepatology, 45(3): 725–734.
-
Durnez A, Verslype C, Nevens F. 2006. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma: A possible progenitor cell origin. Histopathology, 49(2): 138–151.
-
Eisner V, Picard M, Hajnóczky G. 2018. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol, 20(6): 755–765.
-
El-Serag HB, Rudolph KL. 2007. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology, 132(6):2557–2576.
-
Forner A, Vilana R, Ayuso C. 2008. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology, 47(1): 97–104.
-
Hu C, Huang Y, Li L. 2017. Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progress in mammals. Int J Mol Sci, 18(1): 144.
-
Lima AR, Santos L, Correia M. 2018. Dynamin-related protein 1 at the crossroads of cancer. Genes, 9(2): 115.
-
Ma M, Lin XH, Liu HH, Zhang R, Chen RX. 2020. Suppression of DRP1 mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy. Oncol Rep, 43(3): 1010–1018.
-
Nault JC, Calderaro J, Di Tommaso L, Balabaud C, Zafrani ES, Bioulac-Sage P, Roncalli M, Zucman-Rossi J. 2014. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology, 60(6): 1983–1992.
-
Qian W, Wang J, Van Houten B. 2013. The role of dynamin-related protein 1 in cancer growth: A promising therapeutic target? Expert Opin Ther Targets, 17(9): 997–1001.
-
Rehman J, Zhang HJ, Toth PT. 2012. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J, 26(6): 2175–2186.
-
Roskams T, Kojiro M. 2010. Pathology of early hepatocellular carcinoma: Conventional and molecular diagnosis. Semin Liver Dis, 30(1): 17–25.
-
Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S. 2015. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet, 47(5): 505–511.
-
Shen F, Gai J, Xing J. 2018. Dynasore suppresses proliferation and induces apoptosis of the non-small-cell lung cancer cell line A549. Biochem Biophys Res Commun, 495(1): 1158–1166.
-
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. 2019. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 16(10): 589–604.
-
Zhai J, Wang Y, Yang F, Hu J, Qi Q, Zhang Y. 2014. DRP-1, ezrin, and E-cadherin expression and their association with esophageal squamous cell carcinoma. Oncol Lett, 8(1): 133–138.
-
Zhao J, Zhang J, Yu M. 2013. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene, 32(40): 4814–4824.
-
Zhao T, Guo BJ, Xiao CL, Chen JJ, Lü C, Fang FF, Li B. 2021. Aerobic exercise suppresses hepatocellular carcinoma by downregulating dynamin-related protein 1 through the PI3K/AKT pathway. J Integr Med, 19(5): 418–427.