Increased expression of GIPC2 in colon adenocarcinoma is associated with a favorable prognosis and high levels of immune cell infiltration

Kang,Min; Su,Zhaoran

doi:10.3892/or.2023.8503

Increased expression of GIPC2 in colon adenocarcinoma is associated with a favorable prognosis and high levels of immune cell infiltration

Authors:
- Min Kang
- Zhaoran Su
View Affiliations

Affiliations: Department of Pathology, People's Hospital of Tongling City, Tongling, Anhui 244000, P.R. China, Department of Gastrointestinal Surgery, People's Hospital of Tongling City, Tongling, Anhui 244000, P.R. China
Published online on: February 15, 2023 https://doi.org/10.3892/or.2023.8503
Article Number: 66
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gα‑interacting protein C‑terminus PDZ‑domain‑containing family member 2 (GIPC2) serves an important role in the development of digestive tract tumors; however, its role in colon adenocarcinoma (COAD) has yet to be elucidated. In the present study, data were retrieved from The Cancer Genome Atlas database to investigate the association between GIPC2 expression and prognosis, as well as the levels of tumor‑infiltrating immune cells. Immunohistochemical analysis was subsequently performed on 22 pairs of COAD and adjacent normal colon tissues, which were collected during surgery, to verify GIPC2 protein expression. The results showed that the positive rate in the normal intestinal mucosa group (18/22, 81.82%) was significantly higher than that in the COAD group (3/22, 13.64%, χ²=20.497, P<0.001). Gene set enrichment analysis was used to predict the signaling pathways regulated by GIPC2 in COAD, whereas the CIBERSORT algorithm was used to analyze the association between GIPC2 expression and immune cell infiltration. The expression levels of GIPC2 were revealed to be significantly downregulated in COAD compared with in normal colon tissues (P<0.05). Notably, the overall survival (P=0.004), disease‑specific survival (P=0.003) and progression‑free interval (P=0.011) rates of the group with high GIPC2 expression were higher compared with those in the group with low GIPC2 expression. In addition, the results of the regression analysis suggested that GIPC2 was an independent prognostic factor for COAD (P=0.007). The expression levels of GIPC2 were significantly associated with tumor stage, lymph node status and lymphatic invasion, and GIPC2 expression was enriched in ‘cell cycle checkpoints’, ‘DNA replication’ and ‘mitosis‑associated signaling pathways’. In addition, a positive association was observed between high GIPC2 expression and levels of infiltrating immune cells. Moreover, the expression of immune checkpoint‑associated genes was significantly higher in the group with low GIPC2 expression. Taken together, the findings of the present study demonstrated that high expression levels of GIPC2 were associated with a favorable prognosis and increased infiltration of immune cells in COAD; therefore, GIPC2 may serve as a biomarker to assess prognosis and the level of immune cell infiltration in patients with COAD.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Shawki S, Ashburn J, Signs SA and Huang E: Colon cancer: Inflammation-associated cancer. Surg Oncol Clin N Am. 27:269–287. 2018. View Article : Google Scholar : PubMed/NCBI
3	Wu C: Systemic therapy for colon cancer. Surg Oncol Clin N Am. 27:235–242. 2018. View Article : Google Scholar : PubMed/NCBI
4	Mody K and Bekaii-Saab T: Clinical trials and progress in metastatic colon cancer. Surg Oncol Clin N Am. 27:349–365. 2018. View Article : Google Scholar : PubMed/NCBI
5	Bao X, Zhang H, Wu W, Cheng S, Dai X, Zhu X, Fu Q, Tong Z, Liu L, Zheng Y, et al: Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy. J Immunother Cancer. 8:e0014372020. View Article : Google Scholar : PubMed/NCBI
6	Ruan H, Leibowitz BJ, Zhang L and Yu J: Immunogenic cell death in colon cancer prevention and therapy. Mol Carcinog. 59:783–793. 2020. View Article : Google Scholar : PubMed/NCBI
7	Lichtenstern CR, Ngu RK, Shalapour S and Karin M: Immunotherapy, inflammation and colorectal cancer. Cells. 9:6182020. View Article : Google Scholar : PubMed/NCBI
8	Katoh M: GIPC gene family (review). Int J Mol Med. 9:585–589. 2002.PubMed/NCBI
9	Katoh M: Functional proteomics, human genetics and cancer biology of GIPC family members. Exp Mol Med. 45:e262013. View Article : Google Scholar : PubMed/NCBI
10	Saitoh T, Mine T and Katoh M: Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2. Int J Oncol. 20:577–582. 2002.PubMed/NCBI
11	De Marco N, Tussellino M, Carotenuto R, Ronca R, Rizzolio S, Biffo S and Campanella C: Eukaryotic initiation factor eIF6 modulates the expression of Kermit 2/XGIPC in IGF-regulated eye development. Dev Biol. 427:148–154. 2017. View Article : Google Scholar : PubMed/NCBI
12	Tussellino M, De Marco N, Campanella C and Carotenuto R: Involvement of the eukaryotic initiation factor 6 and kermit2/gipc2 in Xenopus laevis pronephros formation. Int J Dev Biol. 56:357–362. 2012. View Article : Google Scholar : PubMed/NCBI
13	Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D and van Roy F: The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 7:1267–1278. 2001. View Article : Google Scholar : PubMed/NCBI
14	Wang LH, Kalb RG and Strittmatter SM: A PDZ protein regulates the distribution of the transmembrane semaphorin, M-SemF. J Biol Chem. 274:14137–14146. 1999. View Article : Google Scholar : PubMed/NCBI
15	Wang C, He Y, You Z and Chen X: TMSB10 promotes progression of clear cell renal cell carcinoma via JUN transcription regulation. Ann Clin Lab Sci. 52:230–239. 2022.PubMed/NCBI
16	Peng W, Li W, Zhang X, Cen W and Liu Y: The intercorrelation among CCT6A, CDC20, CCNB1, and PLK1 expressions and their clinical value in papillary thyroid carcinoma prognostication. J Clin Lab Anal. 36:e246092022. View Article : Google Scholar : PubMed/NCBI
17	Sturm G, Finotello F, Petitprez F, Zhang JD, Baumbach J, Fridman WH, List M and Aneichyk T: Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology. Bioinformatics. 35:i436–i445. 2019. View Article : Google Scholar : PubMed/NCBI
18	R Core Team, . R: A language and environment for statistical computing. R Foundation for Statistical Computing; Vienna, Austria: 2020, https://www.r-project.org/
19	Kirikoshi H and Katoh M: Up-regulation of GIPC2 in human gastric cancer. Int J Oncol. 20:1183–1187. 2020.PubMed/NCBI
20	Wang L, Wang J, Yin X, Guan X, Li Y, Xin C and Liu J: GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling. Oncogene. 41:2609–2623. 2022. View Article : Google Scholar : PubMed/NCBI
21	Liu Z, Wan Y, Yang M, Qi X, Dong Z, Huang J and Xu J: Identification of methylation-driven genes related to the prognosis of papillary renal cell carcinoma: A study based on the cancer genome atlas. Cancer Cell Int. 20:2352020. View Article : Google Scholar : PubMed/NCBI
22	Dong Y, Huang Y, Fan C, Wang L, Zhang R, Li W, Guo Z, Wang D and Zheng Z: GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma. Cell Death Dis. 12:4442021. View Article : Google Scholar : PubMed/NCBI
23	Liu X and Fuentes EJ: Emerging themes in PDZ domain signaling: Structure, function, and inhibition. Int Rev Cell Mol Biol. 343:129–218. 2019. View Article : Google Scholar : PubMed/NCBI
24	Khan Z and Lafon M: PDZ domain-mediated protein interactions: Therapeutic targets in neurological disorders. Curr Med Chem. 21:2632–2641. 2014. View Article : Google Scholar : PubMed/NCBI
25	Tso PH, Wang Y, Wong SY, Poon LS, Chan AS and Wong YH: RGS19 enhances cell proliferation through its C-terminal PDZ motif. Cell Signal. 22:1700–1707. 2010. View Article : Google Scholar : PubMed/NCBI
26	Liu Y, Lou W, Chen G, Ding B, Kuang J, Zhang Y, Wang C, Duan S, Deng Y and Lu X: Genome-wide screening for the G-protein-coupled receptor (GPCR) pathway-related therapeutic gene RGS19 (regulator of G protein signaling 19) in bladder cancer. Bioengineered. 12:5892–5903. 2021. View Article : Google Scholar : PubMed/NCBI
27	Ji YR, Kim MO, Kim SH, Yu DH, Shin MJ, Kim HJ, Yuh HS, Bae KB, Kim JY, Park HD, et al: Effects of regulator of G protein signaling 19 (RGS19) on heart development and function. J Biol Chem. 285:28627–28634. 2010. View Article : Google Scholar : PubMed/NCBI
28	Cancer Genome Atlas Research Network, . Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar : PubMed/NCBI
29	Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, et al: Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 485:502–506. 2012. View Article : Google Scholar : PubMed/NCBI
30	Cancer Genome Atlas Network, . Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar : PubMed/NCBI
31	McGowan CH: Checking in on Cds1 (Chk2): A checkpoint kinase and tumor suppressor. Bioessays. 24:502–511. 2002. View Article : Google Scholar : PubMed/NCBI
32	Li S, Ma J, Si Y, Cheng S, Hu M, Zhi X, Li B, Yu H and Jiang WG: Differential expression and functions of Ehm2 transcript variants in lung adenocarcinoma. Int J Oncol. 54:1747–1758. 2019.PubMed/NCBI
33	Quan J, Bode AM and Luo X: ACSL family: The regulatory mechanisms and therapeutic implications in cancer. Eur J Pharmacol. 909:1743972021. View Article : Google Scholar : PubMed/NCBI
34	Ma W, Li T, Wu S, Li J, Wang X and Li H: LOX and ACSL5 as potential relapse markers for pancreatic cancer patients. Cancer Biol Ther. 20:787–798. 2019. View Article : Google Scholar : PubMed/NCBI
35	Hartmann F, Sparla D, Tute E, Tamm M, Schneider U, Jeon MK, Kasperk R, Gassler N and Kaemmerer E: Low acyl-CoA synthetase 5 expression in colorectal carcinomas is prognostic for early tumour recurrence. Pathol Res Pract. 213:261–266. 2017. View Article : Google Scholar : PubMed/NCBI
36	Jeanneteau F, Guillin O, Diaz J, Griffon N and Sokoloff P: GIPC recruits GAIP (RGS19) to attenuate dopamine D2 receptor signaling. Mol Biol Cell. 15:4926–4937. 2004. View Article : Google Scholar : PubMed/NCBI
37	Ding X, Philip S, Martin BK, Pang Y, Burkett S, Swing DA, Pamala C, Ritt DA, Zhou M, Morrison DK, et al: Survival of BRCA2-deficient cells is promoted by GIPC3, a novel genetic interactor of BRCA2. Genetics. 207:1335–1345. 2017. View Article : Google Scholar : PubMed/NCBI
38	Williams GH and Stoeber K: The cell cycle and cancer. J Pathol. 226:352–364. 2012. View Article : Google Scholar : PubMed/NCBI
39	Topalian SL, Taube JM, Anders RA and Pardoll DM: Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 16:275–287. 2016. View Article : Google Scholar : PubMed/NCBI
40	Galluzzi L, Humeau J, Buqué A, Zitvogel L and Kroemer G: Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 17:725–741. 2020. View Article : Google Scholar : PubMed/NCBI
41	Funes SC, Manrique de Lara A, Altamirano-Lagos MJ, Mackern-Oberti JP, Escobar-Vera J and Kalergis AM: Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy. Autoimmun Rev. 18:359–368. 2019. View Article : Google Scholar : PubMed/NCBI
42	Zhang Y and Zheng J: Functions of immune checkpoint molecules beyond immune evasion. Adv Exp Med Biol. 1248:201–226. 2020. View Article : Google Scholar : PubMed/NCBI