Diacylglycerol Kinase Alpha is a Proliferation Marker of Intrahepatic Cholangiocarcinoma Associated with the Prognosis

Overview

Journal Cancer Med

Specialty Oncology

Date 2024 May 8

PMID 38716625

Authors

Shunsuke Shichi

Ko Sugiyama

Yoh Asahi

Chisato Shirakawa

Hiroki Nakamoto

Saori Kimura

Kazuki Wakizaka

Takeshi Aiyama

Akihisa Nagatsu

Tatsuya Orimo

Tatsuhiko Kakisaka

Akinobu Taketomi

Affiliations

Soon will be listed here.

Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) has a high recurrence rate and a poor prognosis. Thus, the development of effective treatment and prognostic biomarkers is required. High expression of diacylglycerol kinase alpha (DGKα) is a prognostic factor for the recurrence of hepatocellular carcinoma. However, the relationship between DGKα expression and prognosis in ICC has not been reported.

Methods: Immunohistochemistry (IHC) with anti-DGKα antibody was performed on surgical specimens of ICC (n = 69). First, DGKα expression in cancer cells was qualitatively classified into four groups (-, 1+, 2+, 3+) and divided into two groups (DGKα- and DGKα+1 + to 3+). The relationship between clinical features and DGKα expression was analyzed. Second, Ki-67 expression was evaluated as a cell proliferation marker. The number of Ki-67-positive cells was counted, and the relationship with DGKα expression was examined.

Results: DGKα IHC divided the patients into a DGKα+ group (1+: n = 15; 2+: n = 5; 3+: n = 5) and a DGKα- group (-: n = 44). In the DGKα+ group, patients were older and had advanced disease. Both overall survival and recurrence-free survival (RFS) were significantly worse in the DGKα+ patients. DGKα+ was identified as an independent prognostic factor for RFS by multivariate analysis. Furthermore, the number of Ki-67-positive cells increased in association with the staining levels of DGKα.

Conclusion: Pathological DGKα expression in ICC was a cancer proliferation marker associated with recurrence. This suggests that DGKα may be a potential therapeutic target for ICC.

Citing Articles

Overexpression of proteasome 26S subunit non-ATPase 6 protein and its clinicopathological significance in intrahepatic cholangiocarcinoma.

Tang Z, Tang Y, Qin K, Li Q, Chen G, Huang Y World J Hepatol. 2024; 16(11):1282-1289.

PMID: 39606161 PMC: 11586755. DOI: 10.4254/wjh.v16.i11.1282.

Diacylglycerol kinase alpha is a proliferation marker of intrahepatic cholangiocarcinoma associated with the prognosis.

Shichi S, Sugiyama K, Asahi Y, Shirakawa C, Nakamoto H, Kimura S Cancer Med. 2024; 13(9):e7238.

PMID: 38716625 PMC: 11077429. DOI: 10.1002/cam4.7238.

References

Shichi S, Sugiyama K, Asahi Y, Shirakawa C, Nakamoto H, Kimura S . Diacylglycerol kinase alpha is a proliferation marker of intrahepatic cholangiocarcinoma associated with the prognosis. Cancer Med. 2024; 13(9):e7238. PMC: 11077429. DOI: 10.1002/cam4.7238. View

Sano M, Kaneko M, Suzuki H, Kato Y . Establishment and Epitope Mapping of Anti-Diacylglycerol Kinase α Monoclonal Antibody DaMab-8 for Immunohistochemical Analyses. Monoclon Antib Immunodiagn Immunother. 2019; 39(1):1-5. PMC: 7044760. DOI: 10.1089/mab.2019.0004. View

Sakane F, Hoshino F, Ebina M, Sakai H, Takahashi D . The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers (Basel). 2021; 13(20). PMC: 8534027. DOI: 10.3390/cancers13205190. View

DeOliveira M, Cunningham S, Cameron J, Kamangar F, Winter J, Lillemoe K . Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007; 245(5):755-62. PMC: 1877058. DOI: 10.1097/01.sla.0000251366.62632.d3. View

Inoue K, Makuuchi M, Takayama T, Torzilli G, Yamamoto J, Shimada K . Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery. 2000; 127(5):498-505. DOI: 10.1067/msy.2000.104673. View

Bektas H, Yeyrek C, Kleine M, Vondran F, Timrott K, Schweitzer N . Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience. J Hepatobiliary Pancreat Sci. 2014; 22(2):131-7. DOI: 10.1002/jhbp.158. View

Weber S, Jarnagin W, Klimstra D, DeMatteo R, Fong Y, Blumgart L . Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg. 2001; 193(4):384-91. DOI: 10.1016/s1072-7515(01)01016-x. View

Yamaki A, Akiyama R, Murakami C, Takao S, Murakami Y, Mizuno S . Diacylglycerol kinase α-selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines. J Cell Biochem. 2018; 120(6):10043-10056. DOI: 10.1002/jcb.28288. View

Yoh T, Hatano E, Seo S, Okuda Y, Fuji H, Ikeno Y . Long-Term Survival of Recurrent Intrahepatic Cholangiocarcinoma: The Impact and Selection of Repeat Surgery. World J Surg. 2017; 42(6):1848-1856. DOI: 10.1007/s00268-017-4387-7. View

10.

Olenchock B, Guo R, Carpenter J, Jordan M, Topham M, Koretzky G . Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol. 2006; 7(11):1174-81. DOI: 10.1038/ni1400. View

11.

Kudo M, Izumi N, Kokudo N, Sakamoto M, Shiina S, Takayama T . Report of the 21st Nationwide Follow-up Survey of Primary Liver Cancer in Japan (2010-2011). Hepatol Res. 2020; 51(4):355-405. DOI: 10.1111/hepr.13612. View

12.

Orimo T, Kamiyama T, Mitsuhashi T, Kamachi H, Yokoo H, Wakayama K . Impact of tumor localization on the outcomes of surgery for an intrahepatic cholangiocarcinoma. J Gastroenterol. 2018; 53(11):1206-1215. DOI: 10.1007/s00535-018-1469-8. View

13.

Liu K, Kunii N, Sakuma M, Yamaki A, Mizuno S, Sato M . A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response. J Lipid Res. 2016; 57(3):368-79. PMC: 4766986. DOI: 10.1194/jlr.M062794. View

14.

Takeishi K, Taketomi A, Shirabe K, Toshima T, Motomura T, Ikegami T . Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway. J Hepatol. 2012; 57(1):77-83. DOI: 10.1016/j.jhep.2012.02.026. View

15.

Benson A, DAngelica M, Abrams T, Abbott D, Ahmed A, Anaya D . NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023. J Natl Compr Canc Netw. 2023; 21(7):694-704. DOI: 10.6004/jnccn.2023.0035. View

16.

Fu L, Li S, Xiao W, Yu K, Li S, Yuan S . DGKA Mediates Resistance to PD-1 Blockade. Cancer Immunol Res. 2021; 9(4):371-385. DOI: 10.1158/2326-6066.CIR-20-0216. View

17.

Spolverato G, Kim Y, Alexandrescu S, Marques H, Lamelas J, Aldrighetti L . Management and Outcomes of Patients with Recurrent Intrahepatic Cholangiocarcinoma Following Previous Curative-Intent Surgical Resection. Ann Surg Oncol. 2015; 23(1):235-43. DOI: 10.1245/s10434-015-4642-9. View

18.

Zhang X, Beal E, Bagante F, Chakedis J, Weiss M, Popescu I . Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg. 2017; 105(7):848-856. DOI: 10.1002/bjs.10676. View

19.

Okada N, Sugiyama K, Shichi S, Shirai Y, Goto K, Sakane F . Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade. Cancer Immunol Immunother. 2021; 71(4):889-903. PMC: 10991887. DOI: 10.1007/s00262-021-03041-z. View