Skip to content
2000
image of Transcriptomic Landscape of Colorectal Mucinous Adenocarcinoma has Similarity with Intestinal Goblet Cell Differentiation

Abstract

Introduction

Colorectal mucinous adenocarcinoma (MC) differs from adenocarcinoma (AD) in clinical features and molecular characteristics. The current treatment of colorectal MC is not precise enough, and the molecular characteristics remain unclear. The study aims to explore the difference between colorectal MC and AD on the transcriptome level for the possibility of treating colorectal MC precisely.

Methods

The data of colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database was assessed, and then differential analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify the differential hub RNAs between colorectal MC and AD. Differential hub lncRNAs and hub RNA of significant modules were validated by quantitative real-time PCR (qRT-PCR) among different colon cancer cell lines.

Results

In total, 1680 differential expressed RNAs (DERs) were found by comparing colorectal MC (52, 13.3%) with AD (340, 86.7%). Through the WGCNA, a mucin-associated RNA module was identified, while some others might be associated with unique immune progress. Finally, 6 differential hub RNAs in the mucin-associated RNA module ( and ) were validated by qRT-PCR and showed higher expression levels in mucin-producing colorectal cell lines (Ls174T and HT-29).

Conclusion

This study suggests that clinical treatments for colorectal MC should be differentiated from AD. Further exploration of enterocyte (goblet cell) differentiation with tumor genesis and the distinct immune progression of MC may help to identify key therapeutic targets for colorectal MC. Further research on the application of immunotherapy to colorectal MC is needed.

Loading

Article metrics loading...

/content/journals/cg/10.2174/0113892029312303240821080358
2024-09-02
2024-10-15
Loading full text...

Full text loading...

References

  1. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  2. Luo C. Cen S. Ding G. Wu W. Mucinous colorectal adenocarcinoma: Clinical pathology and treatment options. Cancer Commun. 2019 39 1 1 13 10.1186/s40880‑019‑0361‑0 30922401
    [Google Scholar]
  3. Hugen N. van Beek J.J.P. de Wilt J.H.W. Nagtegaal I.D. Insight into mucinous colorectal carcinoma: Clues from etiology. Ann. Surg. Oncol. 2014 21 9 2963 2970 10.1245/s10434‑014‑3706‑6 24728741
    [Google Scholar]
  4. Benesch M.G.K. Mathieson A. Epidemiology of mucinous adenocarcinomas. Cancers 2020 12 11 3193 10.3390/cancers12113193 33143115
    [Google Scholar]
  5. Hyngstrom J.R. Hu C.Y. Xing Y. You Y.N. Feig B.W. Skibber J.M. Rodriguez-Bigas M.A. Cormier J.N. Chang G.J. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the National Cancer Data Base. Ann. Surg. Oncol. 2012 19 9 2814 2821 10.1245/s10434‑012‑2321‑7 22476818
    [Google Scholar]
  6. Negri F.V. Wotherspoon A. Cunningham D. Norman A.R. Chong G. Ross P.J. Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer. Ann. Oncol. 2005 16 8 1305 1310 10.1093/annonc/mdi244 15857840
    [Google Scholar]
  7. Kim S.H. Shin S.J. Lee K.Y. Kim H. Kim T.I. Kang D.R. Hur H. Min B.S. Kim N.K. Chung H.C. Roh J.K. Ahn J.B. Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: A retrospective cohort study. Ann. Surg. Oncol. 2013 20 11 3407 3413 10.1245/s10434‑013‑3169‑1 23943026
    [Google Scholar]
  8. Leopoldo S. Lorena B. Cinzia A. Gabriella D.C. Angela Luciana B. Renato C. Antonio M. Carlo S. Cristina P. Stefano C. Maurizio T. Luigi R. Cesare B. Two subtypes of mucinous adenocarcinoma of the colorectum: Clinicopathological and genetic features. Ann. Surg. Oncol. 2008 15 5 1429 1439 10.1245/s10434‑007‑9757‑1 18301950
    [Google Scholar]
  9. Hugen N. Simons M. Halilović A. van der Post R.S. Bogers A.J. Marijnissen-van Zanten M.A.J. de Wilt J.H.W. Nagtegaal I.D. The molecular background of mucinous carcinoma beyond MUC2. J. Pathol. Clin. Res. 2015 1 1 3 17 10.1002/cjp2.1 27499889
    [Google Scholar]
  10. Huang L. Luo S. Zhang X. Cai Y. Xue F. Hu H. Zeng Z. Lin T. Wang F. Wang W. Zhang S. Kang L. Distinct genomic landscape of colorectal mucinous carcinoma determined via comprehensive genomic profiling: Steps to a new treatment strategy. Front. Oncol. 2021 11 603564 10.3389/fonc.2021.603564 34026601
    [Google Scholar]
  11. Stark R. Grzelak M. Hadfield J. RNA sequencing: The teenage years. Nat. Rev. Genet. 2019 20 11 631 656 10.1038/s41576‑019‑0150‑2 31341269
    [Google Scholar]
  12. Langfelder P. Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008 9 1 559 10.1186/1471‑2105‑9‑559 19114008
    [Google Scholar]
  13. Long J. Huang S. Bai Y. Mao J. Wang A. Lin Y. Yang X. Wang D. Lin J. Bian J. Yang X. Sang X. Wang X. Zhao H. Transcriptional landscape of cholangiocarcinoma revealed by weighted gene coexpression network analysis. Brief. Bioinform. 2021 22 4 bbaa224 10.1093/bib/bbaa224 33051665
    [Google Scholar]
  14. Mercer T.R. Dinger M.E. Mattick J.S. Long non-coding RNAs: Insights into functions. Nat. Rev. Genet. 2009 10 3 155 159 10.1038/nrg2521 19188922
    [Google Scholar]
  15. Isoda T. Moore A.J. He Z. Chandra V. Aida M. Denholtz M. Piet van Hamburg J. Fisch K.M. Chang A.N. Fahl S.P. Wiest D.L. Murre C. Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate. Cell 2017 171 1 103 119.e18 10.1016/j.cell.2017.09.001 28938112
    [Google Scholar]
  16. Schmitt A.M. Chang H.Y. Long noncoding RNAs in cancer pathways. Cancer Cell 2016 29 4 452 463 10.1016/j.ccell.2016.03.010 27070700
    [Google Scholar]
  17. Winkle M. El-Daly S.M. Fabbri M. Calin G.A. Noncoding RNA therapeutics — Challenges and potential solutions. Nat. Rev. Drug Discov. 2021 20 8 629 651 10.1038/s41573‑021‑00219‑z 34145432
    [Google Scholar]
  18. Benson A.B. Venook A.P. Al-Hawary M.M. Arain M.A. Chen Y.J. Ciombor K.K. Cohen S. Cooper H.S. Deming D. Farkas L. Garrido-Laguna I. Grem J.L. Gunn A. Hecht J.R. Hoffe S. Hubbard J. Hunt S. Johung K.L. Kirilcuk N. Krishnamurthi S. Messersmith W.A. Meyerhardt J. Miller E.D. Mulcahy M.F. Nurkin S. Overman M.J. Parikh A. Patel H. Pedersen K. Saltz L. Schneider C. Shibata D. Skibber J.M. Sofocleous C.T. Stoffel E.M. Stotsky-Himelfarb E. Willett C.G. Gregory K.M. Gurski L.A. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw. 2021 19 3 329 359 10.6004/jnccn.2021.0012 33724754
    [Google Scholar]
  19. Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014 15 12 550 10.1186/s13059‑014‑0550‑8 25516281
    [Google Scholar]
  20. Reimand J. Isserlin R. Voisin V. Kucera M. Tannus-Lopes C. Rostamianfar A. Wadi L. Meyer M. Wong J. Xu C. Merico D. Bader G.D. Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap. Nat. Protoc. 2019 14 2 482 517 10.1038/s41596‑018‑0103‑9 30664679
    [Google Scholar]
  21. Reimand J Kull M Peterson H Hansen J Vilo J. g:Profiler--a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 2007 35 W193 W200
    [Google Scholar]
  22. Friedman J. Hastie T. Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Softw. 2010 33 1 1 22 10.18637/jss.v033.i01 20808728
    [Google Scholar]
  23. Niv Y. Byrd J.C. Ho S.B. Dahiya R. Kim Y.S. Mucin synthesis and secretion in relation to spontaneous differentiation of colon cancer cells in vitro. Int. J. Cancer 1992 50 1 147 152 10.1002/ijc.2910500129 1728605
    [Google Scholar]
  24. Gu Y. Zhang L. Yang H. Zhuang J. Sun Z. Guo J. Guan M. Nanosecond pulsed electric fields impair viability and mucin expression in mucinous colorectal carcinoma cell. Bioelectrochemistry 2021 141 107844 10.1016/j.bioelechem.2021.107844 34052542
    [Google Scholar]
  25. Tom B.H. Rutzky L.P. Jakstys M.M. Oyasu R. Kaye C.I. Kahan B.D. Human colonic adenocarcinoma cells. In Vitro 1976 12 3 180 191 10.1007/BF02796440 1262041
    [Google Scholar]
  26. Berg K.C.G. Eide P.W. Eilertsen I.A. Johannessen B. Bruun J. Danielsen S.A. Bjørnslett M. Meza-Zepeda L.A. Eknæs M. Lind G.E. Myklebost O. Skotheim R.I. Sveen A. Lothe R.A. Multi-omics of 34 colorectal cancer cell lines - A resource for biomedical studies. Mol. Cancer 2017 16 1 116 10.1186/s12943‑017‑0691‑y 28683746
    [Google Scholar]
  27. Livak K.J. Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001 25 4 402 408 10.1006/meth.2001.1262 11846609
    [Google Scholar]
  28. Jonckheere N. Skrypek N. Van Seuningen I. Mucins and tumor resistance to chemotherapeutic drugs. Biochim. Biophys. Acta 2014 1846 1 142 151 24785432
    [Google Scholar]
  29. Schwartz B. Bresalier R.S. Kim Y.S. The role of mucin in colon‐cancer metastasis. Int. J. Cancer 1992 52 1 60 65 10.1002/ijc.2910520113 1323540
    [Google Scholar]
  30. Sinicrope F.A. Rego R.L. Foster N. Sargent D.J. Windschitl H.E. Burgart L.J. Witzig T.E. Thibodeau S.N. Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers. Am. J. Gastroenterol. 2006 101 12 2818 2825 10.1111/j.1572‑0241.2006.00845.x 17026563
    [Google Scholar]
  31. Boland C.R. Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010 138 6 2073 2087.e3 10.1053/j.gastro.2009.12.064 20420947
    [Google Scholar]
  32. Reynolds I.S. O’Connell E. Fichtner M. McNamara D.A. Kay E.W. Prehn J.H.M. Furney S.J. Burke J.P. Mucinous adenocarcinoma of the colon and rectum: A genomic analysis. J. Surg. Oncol. 2019 120 8 1427 1435 10.1002/jso.25764 31729037
    [Google Scholar]
  33. Reynolds I.S. Thomas V. O’Connell E. Fichtner M. McNamara D.A. Kay E.W. Prehn J.H.M. Burke J.P. Furney S.J. Mucinous adenocarcinoma of the rectum: A whole genome sequencing study. Front. Oncol. 2020 10 1682 10.3389/fonc.2020.01682 32984045
    [Google Scholar]
  34. Zhang X. Zuo J. Wang L. Han J. Feng L. Wang Y. Fan Z. Identification of differentially expressed genes between mucinous adenocarcinoma and other adenocarcinoma of colorectal cancer using bioinformatics analysis. J. Int. Med. Res. 2020 48 8 10.1177/0300060520949036 32840168
    [Google Scholar]
  35. Johansson M.E. Larsson J.M. Hansson G.C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc. Natl. Acad. Sci. U.S.A. 2011 108 Suppl 1 4659 4665 10.1073/pnas.1006451107
    [Google Scholar]
  36. Beumer J. Clevers H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 2021 22 1 39 53 10.1038/s41580‑020‑0278‑0 32958874
    [Google Scholar]
  37. Gao S. Yan L. Wang R. Li J. Yong J. Zhou X. Wei Y. Wu X. Wang X. Fan X. Yan J. Zhi X. Gao Y. Guo H. Jin X. Wang W. Mao Y. Wang F. Wen L. Fu W. Ge H. Qiao J. Tang F. Tracing the temporal-spatial transcriptome landscapes of the human fetal digestive tract using single-cell RNA-sequencing. Nat. Cell Biol. 2018 20 6 721 734 10.1038/s41556‑018‑0105‑4 29802404
    [Google Scholar]
  38. Noah T.K. Kazanjian A. Whitsett J. Shroyer N.F. SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. Exp. Cell Res. 2010 316 3 452 465 10.1016/j.yexcr.2009.09.020 19786015
    [Google Scholar]
  39. Owen R.P. White M.J. Severson D.T. Braden B. Bailey A. Goldin R. Wang L.M. Ruiz-Puig C. Maynard N.D. Green A. Piazza P. Buck D. Middleton M.R. Ponting C.P. Schuster-Böckler B. Lu X. Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s oesophagus and oesophageal submucosal glands. Nat. Commun. 2018 9 1 4261 10.1038/s41467‑018‑06796‑9 30323168
    [Google Scholar]
  40. Ye D.Z. Kaestner K.H. Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice. Gastroenterology 2009 137 6 2052 2062 10.1053/j.gastro.2009.08.059 19737569
    [Google Scholar]
  41. Shahabi S. Kumaran V. Castillo J. Cong Z. Nandagopal G. Mullen D.J. Alvarado A. Correa M.R. Saizan A. Goel R. Bhat A. Lynch S.K. Zhou B. Borok Z. Marconett C.N. LINC00261 is an epigenetically regulated tumor suppressor essential for activation of the dna damage response. Cancer Res. 2019 79 12 3050 3062 10.1158/0008‑5472.CAN‑18‑2034 30796052
    [Google Scholar]
  42. Shan Y.S. Hsu H.P. Lai M.D. Yen M.C. Fang J.H. Weng T.Y. Chen Y.L. Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model. Oncol. Rep. 2014 32 6 2335 2342 10.3892/or.2014.3544 25322805
    [Google Scholar]
  43. Svobodova S. Topolcan O. Holubec L. Jr Levy M. Pecen L. Svacina S. Parameters of biological activity in colorectal cancer. Anticancer Res. 2011 31 1 373 378 21273626
    [Google Scholar]
  44. Yan C. Yang H. Chen L. Liu R. Shang W. Yuan W. Yang F. Sun Q. Xia L. Clinical significance of mucinous component in colorectal adenocarcinoma: A propensity score-matched study. BMC Cancer 2021 21 1 1286 10.1186/s12885‑021‑09031‑9 34852768
    [Google Scholar]
  45. Verhulst J. Ferdinande L. Demetter P. Ceelen W. Mucinous subtype as prognostic factor in colorectal cancer: A systematic review and meta-analysis. J. Clin. Pathol. 2012 65 5 381 388 10.1136/jclinpath‑2011‑200340 22259177
    [Google Scholar]
  46. Tarantino I. Hüttner F.J. Warschkow R. Schmied B.M. Diener M.K. Ulrich A. Prognostic relevance of mucinous subtype in a population-based propensity score analysis of 40,083 rectal cancer patients. Ann. Surg. Oncol. 2016 23 5 1576 1586 10.1245/s10434‑015‑5029‑7 26714956
    [Google Scholar]
  47. Blank M. Klussmann E. Krüger-Krasagakes S. Schmitt-Gräff A. Stolte M. Bornhoeft G. Stein H. Xing P.X. McKenzie I.F.C. Verstijnen C.P.H.J. Riecken E.O. Hanski C. Expression of MUC2‐mucin in colorectal adenomas and carcinomas of different histological types. Int. J. Cancer 1994 59 3 301 306 10.1002/ijc.2910590302 7927933
    [Google Scholar]
  48. Velcich A. Yang W. Heyer J. Fragale A. Nicholas C. Viani S. Kucherlapati R. Lipkin M. Yang K. Augenlicht L. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 2002 295 5560 1726 1729 10.1126/science.1069094 11872843
    [Google Scholar]
  49. Companioni O. Bonet C. García N. Ramírez-Lázaro M.J. Lario S. Mendoza J. Adrados M.M. Poves E. Espinosa L. Pozo-Kreilinger J.J. Ortega L. Bujanda L. Cosme A. Ferrández A. Muñoz G. Cuatrecasas M. Elizalde I. Andreu V. Paules M.J. Madrigal B. Barrio J. Berdasco M. Calvet X. Sanz-Anquela J.M. Gisbert J.P. González C.A. Sala N. Study Group Genetic variation analysis in a follow‐up study of gastric cancer precursor lesions confirms the association of MUC2 variants with the evolution of the lesions and identifies a significant association with NFKB1 and CD14. Int. J. Cancer 2018 143 11 2777 2786 10.1002/ijc.31839 30171605
    [Google Scholar]
  50. Hugen N. Brown G. Glynne-Jones R. de Wilt J.H.W. Nagtegaal I.D. Advances in the care of patients with mucinous colorectal cancer. Nat. Rev. Clin. Oncol. 2016 13 6 361 369 10.1038/nrclinonc.2015.140 26323388
    [Google Scholar]
  51. Hanski C. Riede E. Gratchev A. Foss H.D. Böhm C. Klussmann E. Hummel M. Mann B. Buhr H.J. Stein H. Kim Y.S. Gum J. Riecken E.O. MUC2 gene suppression in human colorectal carcinomas and their metastases: In vitro evidence of the modulatory role of DNA methylation. Lab. Invest. 1997 77 6 685 695 9426407
    [Google Scholar]
/content/journals/cg/10.2174/0113892029312303240821080358
Loading
/content/journals/cg/10.2174/0113892029312303240821080358
Loading

Data & Media loading...

Supplements

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test