Enhanced RegIV Expression Predicts the Intrinsic 5-fluorouracil (5-FU) Resistance in Advanced Gastric Cancer

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2012 Sep 27

PMID 23010741

Citations 9

Authors

Li-Sha Ying

Jiang-Liu Yu

Xiao-Xiao Lu

Zhi-Qiang Ling

Affiliations

Soon will be listed here.

Abstract

Aim: RegIV, a member of the Regenerating (REG) gene family, may be a marker for the prediction of resistance to 5-fluorouracil (5-FU)-based chemotherapy. However, the relationship between the intrinsic drug resistance of gastric cancer (GC) cells to 5-FU used alone (single FU) or in multidrug therapeutic regimens (5-FU combinations) and RegIV expression has not been investigated.

Methods: The patient cohort comprised 45 patients with primary GC. The chemoresistance of GC cells to therapeutic regimens consisting of single 5-FU or FU combinations was investigated using the ATP-tumor chemosensitivity assay. The level of RegIV mRNA transcripts was determined by real-time reverse transcriptase-PCR. RegIV expression was evaluated as a novel predictive biomarker for the intrinsic drug resistance of primary GC cells to single 5-FU or 5-FU combinations.

Results: Upregulation of RegIV mRNA transcripts was observed in 36 of the 45 tumor specimens and was positively correlated with the invasive depth of the tumor cells (p = 0.000), the clinical stages (p = 0.000) and the in vitro intrinsic drug resistance of primary GC cells to 5-FU (p = 0.000) or 5-FU combinations.

Conclusion: RegIV mRNA transcript level was strongly associated with the intrinsic resistance of GC cells to single 5-FU or 5-FU combinations, suggesting that RegIV may play an important role in the intrinsic resistance of GC cells to 5-FU and that targeted therapy against the RegIV gene could be applied to overcome 5-FU resistance in the treatment of GC.

Citing Articles

THADA inhibits autophagy and increases 5-FU sensitivity in gastric cancer cells via the PI3K/AKT/mTOR signaling pathway.

Lin X, Pan J, Hamoudi H, Yu J Iran J Basic Med Sci. 2024; 27(2):195-202.

PMID: 38234670 PMC: 10790288. DOI: 10.22038/IJBMS.2023.72055.15668.

Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly.

Zhang C, Zhang R, Zhang L, Wang Z, Sun H, Cui Z World J Gastroenterol. 2023; 29(35):5104-5124.

PMID: 37744296 PMC: 10514755. DOI: 10.3748/wjg.v29.i35.5104.

REG4 promotes the proliferation and anti-apoptosis of cancer.

Zheng H, Xue H, Zhang C Front Cell Dev Biol. 2022; 10:1012193.

PMID: 36172286 PMC: 9511136. DOI: 10.3389/fcell.2022.1012193.

Inhibition of G9a promoted 5-fluorouracil (5-FU) induced gastric cancer cell apoptosis ROS/JNK signaling pathway and .

Lou H, Pan H, Huang Z, Wang Z, Wang D RSC Adv. 2022; 9(26):14662-14669.

PMID: 35516300 PMC: 9064134. DOI: 10.1039/c8ra10502b.

The Clinical Significance and Mechanisms of REG4 in Human Cancers.

Zhang J, Zhu Z, Miao Z, Huang X, Sun Z, Xu H Front Oncol. 2021; 10:559230.

PMID: 33489872 PMC: 7819868. DOI: 10.3389/fonc.2020.559230.

References

Fujii M, Kochi M, Takayama T . Recent advances in chemotherapy for advanced gastric cancer in Japan. Surg Today. 2010; 40(4):295-300. DOI: 10.1007/s00595-009-4148-9. View

Mackenzie M, Spithoff K, Jonker D . Systemic therapy for advanced gastric cancer: a clinical practice guideline. Curr Oncol. 2011; 18(4):e202-9. PMC: 3149553. DOI: 10.3747/co.v18i4.737. View

Bishnupuri K, Luo Q, Sainathan S, Kikuchi K, Sureban S, Sabarinathan M . Reg IV regulates normal intestinal and colorectal cancer cell susceptibility to radiation-induced apoptosis. Gastroenterology. 2009; 138(2):616-26, 626.e1-2. PMC: 2819553. DOI: 10.1053/j.gastro.2009.10.050. View

Yasui W, Oue N, Sentani K, Sakamoto N, Motoshita J . Transcriptome dissection of gastric cancer: identification of novel diagnostic and therapeutic targets from pathology specimens. Pathol Int. 2009; 59(3):121-36. DOI: 10.1111/j.1440-1827.2009.02329.x. View

Fedorenko I, Paraiso K, Smalley K . Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011; 82(3):201-9. PMC: 4001781. DOI: 10.1016/j.bcp.2011.05.015. View

Ling Z, Li P, Ge M, Zhao X, Hu F, Fang X . Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer. Int J Mol Med. 2011; 27(5):625-35. DOI: 10.3892/ijmm.2011.640. View

Bishnupuri K, Luo Q, Korzenik J, Henderson J, Houchen C, Anant S . Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes. Cancer Biol Ther. 2006; 5(12):1714-20. DOI: 10.4161/cbt.5.12.3469. View

Sumantran V . Cellular chemosensitivity assays: an overview. Methods Mol Biol. 2011; 731:219-36. DOI: 10.1007/978-1-61779-080-5_19. View

Quintieri L, Fantin M, Vizler C . Identification of molecular determinants of tumor sensitivity and resistance to anticancer drugs. Adv Exp Med Biol. 2007; 593:95-104. DOI: 10.1007/978-0-387-39978-2_10. View

10.

Heiskala K, Arola J, Heiskala M, Andersson L . Expression of Reg IV and Hath1 in neuroendocrine neoplasms. Histol Histopathol. 2009; 25(1):63-72. DOI: 10.14670/HH-25.63. View

11.

Ling Z, Qi C, Lu X, Qian L, Gu L, Zheng Z . Heterogeneity of chemosensitivity in esophageal cancer using ATP-tumor chemosensitivity assay. Acta Pharmacol Sin. 2012; 33(3):401-6. PMC: 4077137. DOI: 10.1038/aps.2011.195. View

12.

Violette S, Festor E, Mitchell V, Adida C, Dussaulx E, Lacorte J . Reg IV, a new member of the regenerating gene family, is overexpressed in colorectal carcinomas. Int J Cancer. 2002; 103(2):185-93. DOI: 10.1002/ijc.10788. View

13.

Mitani Y, Oue N, Matsumura S, Yoshida K, Noguchi T, Ito M . Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy. Oncogene. 2007; 26(30):4383-93. DOI: 10.1038/sj.onc.1210215. View

14.

Pasini F, Fraccon A, De Manzoni G . The role of chemotherapy in metastatic gastric cancer. Anticancer Res. 2011; 31(10):3543-54. View

15.

Shekhar M . Drug resistance: challenges to effective therapy. Curr Cancer Drug Targets. 2011; 11(5):613-23. DOI: 10.2174/156800911795655921. View

16.

Gu Z, Rubin M, Yang Y, DePrimo S, Zhao H, Horvath S . Reg IV: a promising marker of hormone refractory metastatic prostate cancer. Clin Cancer Res. 2005; 11(6):2237-43. DOI: 10.1158/1078-0432.CCR-04-0356. View

17.

Kurbacher C, Cree I . Chemosensitivity testing using microplate adenosine triphosphate-based luminescence measurements. Methods Mol Med. 2005; 110:101-20. DOI: 10.1385/1-59259-869-2:101. View

18.

Tamura H, Ohtsuka M, Washiro M, Kimura F, Shimizu H, Yoshidome H . Reg IV expression and clinicopathologic features of gallbladder carcinoma. Hum Pathol. 2009; 40(12):1686-92. DOI: 10.1016/j.humpath.2009.06.001. View

19.

Blumenthal R, Goldenberg D . Methods and goals for the use of in vitro and in vivo chemosensitivity testing. Mol Biotechnol. 2007; 35(2):185-97. DOI: 10.1007/BF02686104. View

20.

Yuan S, Zhou Z, Liang Y, Fu L, Chen G, Keshari R . [Correlation of chemosensitivity measured by histoculture drug response assay to expression of multidrug resistance genes and proteins in gastric cancer]. Ai Zheng. 2009; 28(4):337-43. View