The lnc-MAPKAPK5-AS1 promotes colon cancer-derived liver metastasis via modulating the tumor microenvironment: an in silico study and immunohistochemistry validation

Abstract

Background: This study aimed to investigate the expression of lnc-MAPKAPK5-AS1 in colon cancer and its clinical implications for prognosis, liver metastasis, and tumor microenvironment (TME) regulation.

Methods: Through integrative analysis of public databases (TCGA, GEO, cBioPortal, David, BioGRID, etc.), we systematically evaluated the roles of lnc-MAPKAPK5-AS1 and MAPKAPK5 in colon cancer development, liver metastasis, immune microenvironment modulation, and associated biological pathways. Immune infiltration patterns were assessed using ESTIMATE, CIBERSORT, and xCell algorithms. MAPKAPK5 protein expression was further validated by immunohistochemistry.

Results:Lnc-MAPKAPK5-AS1 was upregulated in colon cancer tissues and correlated with poor clinical outcomes. Immunohistochemistry confirmed that MAPKAPK5 protein was strongly or moderately expressed in colon cancer tissues. Furthermore, compared with the colon cancer tissues in situ, patients with liver metastasis also showed elevated expression of lnc-MAPKAPK5-AS1. Functional enrichment analysis revealed that differentially expressed genes (DEGs) were primarily involved in amino acid and lipid metabolism pathways. In addition, immune infiltration analysis indicated that lnc-MAPKAPK5-AS1 expression was associated with multiple immune checkpoint inhibitors. The group with high gene expression showed increased infiltration abundance of regulatory T cells, gamma-delta T cells, and CD8⁺ naive T cells.

Conclusions:Lnc-MAPKAPK5-AS1 may serve as a potential oncogenic biomarker in colon cancer. Our findings indicate that its upregulation could contribute to tumor progression and liver metastasis, possibly by remodeling the TME via immune cell modulation, including potential alterations in the proliferation, differentiation, and functional states of key lymphocyte subsets.

Keywords

Colon cancer / liver metastasis / lnc-MAPKAPK5-AS1 / MAPKAPK5 / prognosis

References

[1] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[2] Devesa SS.Variation in colorectal cancer incidence in the united states by subsite of origin.Cancer1993;71:3819-26

[3] Engstrand J,Strömberg C,Freedman J.Colorectal cancer liver metastases - a population-based study on incidence, management and survival.BMC Cancer2018;18:78 PMCID:PMC5769309

[4] Xu R,Zhu B.Disease characteristics and treatment patterns of Chinese patients with metastatic colorectal cancer: a retrospective study using medical records from China.BMC Cancer2020;20:131 PMCID:PMC7029588

[5] Liu SJ,Lim DA,Maher CA.Long noncoding RNAs in cancer metastasis.Nat Rev Cancer2021;21:446-60 PMCID:PMC8288800

[6] Chen S.Long noncoding RNAs: functions and mechanisms in colon cancer.Mol Cancer2020;19:167 PMCID:PMC7697375

[7] Wu K,Song X.LncRNA SLCO4A1-AS1 modulates colon cancer stem cell properties by binding to miR-150-3p and positively regulating SLCO4A1.Lab Invest2021;101:908-20 PMCID:PMC8214995

[8] Chen Q,Ma D.LncRNA GAS6-AS1 facilitates tumorigenesis and metastasis of colorectal cancer by regulating TRIM14 through miR-370-3p/miR-1296-5p and FUS.J Transl Med2022;20:356 PMCID:PMC9373365

[9] Yang T,Shi PC.Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge.J Exp Clin Cancer Res2020;39:139 PMCID:PMC7370515

[10] Ji H,Wang J.Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer proliferation by partly silencing p21 expression.Cancer Sci2019;110:72-85 PMCID:PMC6317943

[11] Gao GF,Reynolds SM.Before and after: comparison of legacy and harmonized TCGA genomic data commons' data.Cell Syst2019;9:24-34.e10 PMCID:PMC6707074

[12] Barrett T,Ledoux P.NCBI GEO: archive for functional genomics data sets-update.Nucleic Acids Res2013;41:D991-5 PMCID:PMC3531084

[13] Oughtred R,Breitkreutz BJ.The BioGRID interaction database: 2019 update.Nucleic Acids Res2019;47:D529-41 PMCID:PMC6324058

[14] Sherman BT,Qiu J.DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update).Nucleic Acids Res2022;50:W216-21 PMCID:PMC9252805

[15] Tang Z,Kang B,Li C.GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses.Nucleic Acids Res2017;45:W98-102 PMCID:PMC5570223

[16] Gao J,Dogrusoz U.Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.Sci Signal2013;6:pl1 PMCID:PMC4160307

[17] Shen W,Zhong X.Sangerbox: a comprehensive, interaction-friendly clinical bioinformatics analysis platform.Imeta2022;1:e36 PMCID:PMC10989974

[18] Aran D,Butte AJ.xCell: digitally portraying the tissue cellular heterogeneity landscape.Genome Biol2017;18:220 PMCID:PMC5688663

[19] Chandrashekar DS,Korla PK.UALCAN: an update to the integrated cancer data analysis platform.Neoplasia2022;25:18-27 PMCID:PMC8788199

[20] Shi Y,Zhang J,Wu S.Identification of tumorigenic and prognostic biomarkers in colorectal cancer based on microRNA expression profiles.Biomed Res Int2020;2020:7136049 PMCID:PMC7424406

[21] Jin W.Novel insights into PARK7 (DJ-1), a potential anti-cancer therapeutic target, and implications for cancer progression.J Clin Med2020;9:1256 PMCID:PMC7288009

[22] Willett W.The search for the causes of breast and colon cancer.Nature1989;338:389-94

[23] Hofseth LJ,Chanda A.Early-onset colorectal cancer: initial clues and current views.Nat Rev Gastroenterol Hepatol2020;17:352-64 PMCID:PMC10711686

[24] Degirolamo C,Palasciano G.Bile acids and colon cancer: solving the puzzle with nuclear receptors.Trends Mol Med2011;17:564-72

[25] Konishi T,Hsu M.Association of preoperative and postoperative serum carcinoembryonic antigen and colon cancer outcome.JAMA Oncol2018;4:309-15 PMCID:PMC5885834

[26] Nakamura Y,Tanabe T.Prognostic impact of preoperatively elevated and postoperatively normalized carcinoembryonic antigen levels following curative resection of stage I-III rectal cancer.Cancer Med2020;9:653-62 PMCID:PMC6970051

[27] Zhao H,Qi J.Increased expression of HOXA11-AS attenuates endometrial decidualization in recurrent implantation failure patients.Mol Ther2022;30:1706-20 PMCID:PMC9077377

[28] Pan X,Feng J.The role of LncRNAs in tumor immunotherapy.Cancer Cell Int2023;23:30 PMCID:PMC9942365

[29] Garrett WS.The gut microbiota and colon cancer.Science2019;364:1133-5

[30] Wu Z,Li L.Identification and validation of ferroptosis-related LncRNA signatures as a novel prognostic model for colon cancer.Front Immunol2021;12:783362 PMCID:PMC8826443

[31] Xu M,Wang J,Wang J.Construction and validation of a cuproptosis-related lncRNA signature as a novel and robust prognostic model for colon adenocarcinoma.Front Oncol2022;12:961213 PMCID:PMC9367690

[32] Li X,Wang W,Lai Y.Constructing a prognostic immune-related lncRNA model for colon cancer.Medicine2022;101:e30447

[33] Yue B,Sun H.A positive feed-forward loop between LncRNA-CYTOR and Wnt/β-catenin signaling promotes metastasis of colon cancer.Mol Ther2018;26:1287-98 PMCID:PMC5993983

[34] Bo H,Li J.High expression of lncRNA AFAP1-AS1 promotes the progression of colon cancer and predicts poor prognosis.J Cancer2018;9:4677-83 PMCID:PMC6299385

[35] Yang Q,Tang C,He J.[Retracted] H19 promotes the migration and invasion of colon cancer by sponging miR-138 to upregulate the expression of HMGA1.Int J Oncol2021;58:26 PMCID:PMC8025963

[36] Cheng B,Zhou Q.LncRNA LINC00662 promotes colon cancer tumor growth and metastasis by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway.J Exp Clin Cancer Res2020;39:5 PMCID:PMC6942292

[37] Shan Y,Pan Y,Liu B.LncRNA SNHG7 sponges miR-216b to promote proliferation and liver metastasis of colorectal cancer through upregulating GALNT1.Cell Death Dis2018;9:722 PMCID:PMC6006356

[38] Wang L,Liu R.Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression.J Exp Clin Cancer Res2021;40:72 PMCID:PMC7891009

[39] Tao L,Mu S,Yan G.LncRNA MAPKAPK5_AS1 facilitates cell proliferation in hepatitis B virus -related hepatocellular carcinoma.Lab Invest2022;102:494-504

[40] Lv E,Yu C,Huang W.Long noncoding RNA MAPKAPK5-AS1 promotes metastasis through regulation miR-376b-5p/ECT2 axis in hepatocellular carcinoma.Dig Liver Dis2023;55:945-54

[41] Meng S,Yan X,Zhang R.LncRNA SNHG6 inhibits cell proliferation and metastasis by targeting ETS1 via the PI3K/AKT/mTOR pathway in colorectal cancer.Mol Med Rep2019;20:2541-8 PMCID:PMC6691244

[42] Lin S,Yang W,Geng C.Silencing of long non-coding RNA colon cancer-associated transcript 2 inhibits the growth and metastasis of gastric cancer through blocking mTOR signaling [Retraction].Onco Targets Ther2022;15:1507-8 PMCID:PMC9748106

[43] Cai Q,Wang W.MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.Sci Adv2021;7:eabi6439 PMCID:PMC8589317

[44] Nakayama M.Mutant p53 in colon cancer.J Mol Cell Biol2019;11:267-76 PMCID:PMC6487790

[45] Polidoro MA,Soldani C.Impact of RAS mutations on the immune infiltrate of colorectal liver metastases: a preliminary study.J Leukoc Biol2020;108:715-21

[46] Kakar S,Sahai V.Clinicopathologic characteristics, CpG island methylator phenotype, and BRAF mutations in microsatellite-stable colorectal cancers without chromosomal instability.Arch Pathol Lab Med2008;132:958-64

[47] Bertocchi A,Ravenda PS.Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.Cancer Cell2021;39:708-24.e11

[48] Wang H,Li R.KIAA1199 drives immune suppression to promote colorectal cancer liver metastasis by modulating neutrophil infiltration.Hepatology2022;76:967-81

[49] Baldin P,Mlecnik B.Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore.J Pathol Clin Res2021;7:27-41 PMCID:PMC7737782

[50] Wang Y,Huang MY.The immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases.Cancer Immunol Immunother2018;67:435-44 PMCID:PMC11028131

[51] Zhou SN,Pan MX.Comparison of immune microenvironment between colon and liver metastatic tissue in colon cancer patients with liver metastasis.Dig Dis Sci2021;66:474-82

[52] Schaafsma E,Cheng C.B cell infiltration is highly associated with prognosis and an immune-infiltrated tumor microenvironment in neuroblastoma.J Cancer Metastasis Treat2021;7:34 PMCID:PMC8389852

[53] Ge J,Zhang G,Li D.New HCC subtypes based on CD8 tex-related lncRNA signature could predict prognosis, immunological and drug sensitivity characteristics of hepatocellular carcinoma.J Hepatocell Carcinoma2024;11:1331-55

[54] Ni H,Diener K.MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase.Biochem Biophys Res Commun1998;243:492-6