PUF60 Promotes Chemoresistance Through Drug Efflux and Reducing Apoptosis in Gastric Cancer

Overview

Journal Int J Med Sci

Date 2025 Jan 9

PMID 39781520

Authors

Qianhui Liu

Yingqiu Song

Jing Su

Shangbin Yang

Qinghai Lian

Tiantian Wang

Hongbo Wei

Jiafeng Fang

Affiliations

Soon will be listed here.

Abstract

Chemotherapy resistance is a great challenge in the treatment of gastric cancer (GC), so it is urgent to explore the prognostic markers of chemoresistance. PUF60 (Poly (U)-binding splicing factor 60) is a nucleic acid-binding protein that has been shown to regulate transcription and link to tumorigenesis in various cancers. However, its biological role and function in chemotherapy resistance of GC is unclear. The expression and prognostic value of PUF60 in GC chemotherapy-resistant patients were analyzed by databases and K-M Plotter. The functional effect of PUF60 on chemoresistance in GC was studied by by RNA interference, CCK8 test, colony formation test and apoptosis detection. Moreover, further validation and mechanism exploration were conducted in clinical samples. PUF60 was highly expressed in both GC and chemoresistant tissues, and was positively correlated with poor prognosis in GC patients treated with 5-fluorouracil (5-FU). In addition, the knockdown of PUF60 significantly reduced the proliferation of human gastric cancer cells and increased sensitivity to chemotherapy drugs, such as 5-FU and cisplatin (CDDP). Mechanistically, PUF60 enhances chemotherapy resistance in gastric cancer (GC) cells by actively excluding chemotherapy drugs via the recombinant ATP Binding Cassette Transporter A1 (ABCA1) and ATP Binding Cassette Subfamily C Member 1 (ABCC1). This process further affects the cell cycle, reduces cell apoptosis, and ultimately promotes resistance to chemotherapy in GC. PUF60 promotes chemoresistance in GC, resulting in poor prognosis of GC patients treated with 5-FU, and providing a new idea for overcoming the chemoresistance in GC.

References

Yan D, An G, Kuo M . C-Jun N-terminal kinase signalling pathway in response to cisplatin. J Cell Mol Med. 2016; 20(11):2013-2019. PMC: 5082413. DOI: 10.1111/jcmm.12908. View

Low K, Ansari M, Abou Jamra R, Clarke A, El Chehadeh S, Fitzpatrick D . PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features. Eur J Hum Genet. 2017; 25(5):552-559. PMC: 5392357. DOI: 10.1038/ejhg.2017.27. View

Low H, Wong Z, Wu B, Kong L, Png C, Cho Y . DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death. Nat Commun. 2021; 12(1):2284. PMC: 8052345. DOI: 10.1038/s41467-021-22638-7. View

Kobayashi S, Hoshino T, Hiwasa T, Satoh M, Rahmutulla B, Tsuchida S . Anti-FIRs (PUF60) auto-antibodies are detected in the sera of early-stage colon cancer patients. Oncotarget. 2016; 7(50):82493-82503. PMC: 5347708. DOI: 10.18632/oncotarget.12696. View

Marin J, Al-Abdulla R, Lozano E, Briz O, Bujanda L, Banales J . Mechanisms of Resistance to Chemotherapy in Gastric Cancer. Anticancer Agents Med Chem. 2015; 16(3):318-34. DOI: 10.2174/1871520615666150803125121. View

Malz M, Bovet M, Samarin J, Rabenhorst U, Sticht C, Bissinger M . Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma. Hepatology. 2014; 60(4):1241-50. DOI: 10.1002/hep.27218. View

Hammond W, Swaika A, Mody K . Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016; 8(1):57-84. PMC: 4699262. DOI: 10.1177/1758834015614530. View

Shannon P, Markiel A, Ozier O, Baliga N, Wang J, Ramage D . Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-504. PMC: 403769. DOI: 10.1101/gr.1239303. View

An J, Luo Z, An W, Cao D, Ma J, Liu Z . Identification of spliceosome components pivotal to breast cancer survival. RNA Biol. 2020; 18(6):833-842. PMC: 8081035. DOI: 10.1080/15476286.2020.1822636. View

10.

Hastings M, Allemand E, Duelli D, Myers M, Krainer A . Control of pre-mRNA splicing by the general splicing factors PUF60 and U2AF(65). PLoS One. 2007; 2(6):e538. PMC: 1888729. DOI: 10.1371/journal.pone.0000538. View

11.

Wang Q, Xiong J, Qiu D, Zhao X, Yan D, Xu W . Inhibition of PARP1 activity enhances chemotherapeutic efficiency in cisplatin-resistant gastric cancer cells. Int J Biochem Cell Biol. 2017; 92:164-172. DOI: 10.1016/j.biocel.2017.08.001. View

12.

Bush J, Li G . Cancer chemoresistance: the relationship between p53 and multidrug transporters. Int J Cancer. 2002; 98(3):323-30. DOI: 10.1002/ijc.10226. View

13.

Long Q, An X, Chen M, Wang N, Sui S, Li Y . Axis Contributes to Tumor Progression and Malignant Phenotypes in Bladder Cancer. Front Oncol. 2020; 10:568015. PMC: 7576680. DOI: 10.3389/fonc.2020.568015. View

14.

Muller B, Bovet M, Yin Y, Stichel D, Malz M, Gonzalez-Vallinas M . Concomitant expression of far upstream element (FUSE) binding protein (FBP) interacting repressor (FIR) and its splice variants induce migration and invasion of non-small cell lung cancer (NSCLC) cells. J Pathol. 2015; 237(3):390-401. DOI: 10.1002/path.4588. View

15.

Wang F, Peng L, Sun Y, Zhang B, Lu S . PUF60 promotes glioblastoma progression through regulation of EGFR stability. Biochem Biophys Res Commun. 2022; 636(Pt 1):190-196. DOI: 10.1016/j.bbrc.2022.10.082. View

16.

Cheng L, Wang P, Yang S, Yang Y, Zhang Q, Zhang W . Identification of genes with a correlation between copy number and expression in gastric cancer. BMC Med Genomics. 2012; 5:14. PMC: 3441862. DOI: 10.1186/1755-8794-5-14. View

17.

Ramakrishna M, Williams L, Boyle S, Bearfoot J, Sridhar A, Speed T . Identification of candidate growth promoting genes in ovarian cancer through integrated copy number and expression analysis. PLoS One. 2010; 5(4):e9983. PMC: 2851616. DOI: 10.1371/journal.pone.0009983. View

18.

Shitara K, Van Cutsem E, Bang Y, Fuchs C, Wyrwicz L, Lee K . Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020; 6(10):1571-1580. PMC: 7489405. DOI: 10.1001/jamaoncol.2020.3370. View

19.

El Chehadeh S, Kerstjens-Frederikse W, Thevenon J, Kuentz P, Bruel A, Thauvin-Robinet C . Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature. Eur J Hum Genet. 2016; 25(1):43-51. PMC: 5159768. DOI: 10.1038/ejhg.2016.133. View

20.

Kajiwara T, Matsushita K, Itoga S, Tamura M, Tanaka N, Tomonaga T . SAP155-mediated c-myc suppressor far-upstream element-binding protein-interacting repressor splicing variants are activated in colon cancer tissues. Cancer Sci. 2012; 104(2):149-56. PMC: 7657139. DOI: 10.1111/cas.12058. View