Skip to main content

Advertisement

SpringerLink
Log in

High FRMD3 expression is prognostic for worse survival in rectal cancer patients treated with CCRT

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Rectal cancer patients can conceivably obtain relief from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before resection, but the stratification of risk and clinical outcomes remains challenging. Therefore, identifying effective predictive biomarkers offers clinicians the opportunity to individually tailor early interventions, which would help optimize therapy.

Methods

Using a public rectal cancer transcriptome dataset (GSE35452), we focused on cytoskeletal protein binding (GO: 0008092)-related genes and identified FERM domain containing 3 (FRMD3) as the most significant differentially expressed gene associated with CCRT resistance. We gathered 172 tumor samples from rectal cancer patients treated with neoadjuvant CCRT accompanied by curative resection and estimated the expression level of FRMD3 using immunohistochemistry.

Results

The results revealed that high FRMD3 immunoexpression was remarkably associated with advanced pre-CCRT and post-CCRT tumor status (p = 0.004 and p < 0.001), pre-CCRT and post-CCRT lymph node metastasis (both p < 0.001), more perineurial invasion (p = 0.023), and a smaller extent of tumor regression (p = 0.018). High FRMD3 immunoexpression was remarkably correlated with inferior disease-specific survival (DSS) (p = 0.0001), local recurrence-free survival (LRFS) (p = 0.0003), and metastasis-free survival (MeFS) (p = 0.0023) at the univariate level. Furthermore, in multivariate analysis, high FRMD3 immunoexpression remained independently predictive of inferior DSS (p = 0.002), LRFS (p = 0.005), and MeFS (p = 0.015).

Conclusion

These results suggest that high FRMD3 expression is related to advanced clinicopathological features and inferior therapeutic responses in rectal cancer patients treated with CCRT, validating the promising prognostic value of FRMD3 expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

The dataset analyzed in the current study is available in the public transcriptome dataset GSE35452 from the GEO database (National Center for Biotechnology Information, Bethesda, MD, USA).

References

  1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70(1):7–30

    Article  PubMed  Google Scholar 

  2. Jemal A et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  3. Fokas E et al (2014) Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol 32(15):1554–1562

    Article  PubMed  Google Scholar 

  4. Cordes N, Meineke V (2003) Cell adhesion-mediated radioresistance (CAM-RR). Extracellular matrix-dependent improvement of cell survival in human tumor and normal cells in vitro. Strahlenther Onkol 179(5):337–344

    Article  PubMed  Google Scholar 

  5. Landowski TH et al (2003) Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells. Oncogene 22(16):2417–2421

    Article  CAS  PubMed  Google Scholar 

  6. Dickreuter E, Cordes N (2017) The cancer cell adhesion resistome: mechanisms, targeting and translational approaches. Biol Chem 398(7):721–735

    Article  CAS  PubMed  Google Scholar 

  7. Ni X et al (2003) Molecular cloning and characterization of the protein 4.1O gene, a novel member of the protein 4.1 family with focal expression in ovary. J Hum Genet 48(2):101–106

    Article  CAS  PubMed  Google Scholar 

  8. Buffon MP et al (2015) FRMD3 gene: its role in diabetic kidney disease. A narrative review. Diabetol Metab Syndr 7:118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Nunomura W et al (1997) Regulation of CD44-protein 4.1 interaction by Ca2+ and calmodulin. Implications for modulation of CD44-ankyrin interaction. J Biol Chem 272(48):30322–30328

    Article  CAS  PubMed  Google Scholar 

  10. Haase D et al (2007) FRMD3, a novel putative tumour suppressor in NSCLC. Oncogene 26(30):4464–4468

    Article  CAS  PubMed  Google Scholar 

  11. Tran YK et al (1999) A novel member of the NF2/ERM/41 superfamily with growth suppressing properties in lung cancer. Cancer Res 59(1):35–43

    CAS  PubMed  Google Scholar 

  12. Pezzolesi MG et al (2009) Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58(6):1403–1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12(1):19–23

    Article  CAS  PubMed  Google Scholar 

  14. Chan TC et al (2020) SLC14A1 prevents oncometabolite accumulation and recruits HDAC1 to transrepress oncometabolite genes in urothelial carcinoma. Theranostics 10(25):11775–11793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kramer-Zucker AG et al (2005) Organization of the pronephric filtration apparatus in zebrafish requires Nephrin, Podocin and the FERM domain protein Mosaic eyes. Dev Biol 285(2):316–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Freedman BI et al (2011) Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans. PLoS Genet 7(6):e1002150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Al-waheeb S et al (2016) Evaluation of associations between single nucleotide polymorphisms in the FRMD3 and CARS genes and diabetic nephropathy in a Kuwaiti population. Genet Mol Res 15:114

    Article  CAS  Google Scholar 

  18. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767

    Article  CAS  PubMed  Google Scholar 

  19. The Cancer Genome Atlas (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–7

  20. O’Donnell KA et al (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843

    Article  CAS  PubMed  Google Scholar 

  21. Watanabe T et al (2014) Prediction of response to preoperative chemoradiotherapy in rectal cancer by using reverse transcriptase polymerase chain reaction analysis of four genes. Dis Colon Rectum 57(1):23–31

    Article  PubMed  Google Scholar 

  22. Murphy JM et al (2020) Targeting focal adhesion kinase in cancer cells and the tumor microenvironment. Exp Mol Med 52(6):877–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Frame MC et al (2010) The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol 11(11):802–814

    Article  CAS  PubMed  Google Scholar 

  24. Dickreuter E et al (2016) Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells. Oncogene 35(11):1353–1362

    Article  CAS  PubMed  Google Scholar 

  25. Vehlow A et al (2017) Adhesion- and stress-related adaptation of glioma radiochemoresistance is circumvented by β1 integrin/JNK co-targeting. Oncotarget 8(30):49224–49237

    Article  PubMed  PubMed Central  Google Scholar 

  26. Meineke V et al (2002) Ionizing radiation modulates cell surface integrin expression and adhesion of COLO-320 cells to collagen and fibronectin in vitro. Strahlenther Onkol 178(12):709–714

    Article  PubMed  Google Scholar 

  27. Bloomgarden ZT (2005) Diabetic nephropathy. Diabetes Care 28(3):745–751

    Article  PubMed  Google Scholar 

  28. Eke I et al (2012) β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest 122(4):1529–1540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ou J et al (2012) αV integrin induces multicellular radioresistance in human nasopharyngeal carcinoma via activating SAPK/JNK pathway. PLoS ONE 7(6):e38737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zeng Y et al (2015) Prognostic significance of interleukin-17 in solid tumors: a meta-analysis. Int J Clin Exp Med 8(7):10515–10536

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rokavec M et al (2014) IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 124(4):1853–1867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ferrao RD, Wallweber HJ, Lupardus PJ (2018) Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation. Elife 7:51

    Article  Google Scholar 

  33. Du W et al (2012) Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway. J Cell Mol Med 16(8):1878–1888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chang L et al (2016) Cancer stem cells and signaling pathways in radioresistance. Oncotarget 7(10):11002–11017

    Article  PubMed  Google Scholar 

  35. Giancotti FG (2013) Mechanisms governing metastatic dormancy and reactivation. Cell 155(4):750–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martini S et al (2013) From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy. Diabetes 62(7):2605–2612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fares J et al (2020) Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 5(1):28

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhou Y et al (2018) Cancer stem cells in progression of colorectal cancer. Oncotarget 9(70):33403–33415

    Article  PubMed  Google Scholar 

  39. Wang J et al (2010) Notch promotes radioresistance of glioma stem cells. Stem Cells 28(1):17–28

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bu P et al (2013) A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell 12(5):602–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yahyanejad S, Theys J, Vooijs M (2016) Targeting Notch to overcome radiation resistance. Oncotarget 7(7):7610–7628

    Article  PubMed  Google Scholar 

  42. Liu WH et al (2020) CD44-associated radioresistance of glioblastoma in irradiated brain areas with optimal tumor coverage. Cancer Med 9(1):350–360

    Article  CAS  PubMed  Google Scholar 

  43. Piao LS et al (2012) CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett 315(2):129–137

    Article  CAS  PubMed  Google Scholar 

  44. Dalerba P et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 104(24):10158–10163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mori T et al (2008) Structural basis for CD44 recognition by ERM proteins. J Biol Chem 283(43):29602–29612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lee H et al (2020) Prominin-1-Radixin axis controls hepatic gluconeogenesis by regulating PKA activity. EMBO Rep 21(11):e49416

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Vishnubalaji R et al (2018) Molecular profiling of ALDH1(+) colorectal cancer stem cells reveals preferential activation of MAPK, FAK, and oxidative stress pro-survival signalling pathways. Oncotarget 9(17):13551–13564

    Article  PubMed  PubMed Central  Google Scholar 

  48. Park SY et al (2019) The JAK2/STAT3/CCND2 Axis promotes colorectal Cancer stem cell persistence and radioresistance. J Exp Clin Cancer Res 38(1):399

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Tzu-Ju Chen and Chia-Lin Chou contributed equally to this work

Authors and Affiliations

  1. Department of Clinical Pathology, Chi Mei Medical Center, 901 Chunghwa Road, Yung Kang Dist., Tainan City, 710, Taiwan

    Tzu-Ju Chen, Hsin-Hwa Tsai, Chien-Feng Li & Hong-Yue Lai

  2. Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan

    Tzu-Ju Chen, Hong-Lin He & Wan-Shan Li

  3. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Tzu-Ju Chen & Wan-Shan Li

  4. Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan

    Chia-Lin Chou & Yu-Feng Tian

  5. Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan

    Cheng-Fa Yeh

  6. Department of Medical Research, Chi Mei Medical Center, 901 Chunghwa Road, Yung Kang Dist., Tainan City, 710, Taiwan

    Ti-Chun Chan, Hsin-Hwa Tsai, Chien-Feng Li & Hong-Yue Lai

  7. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Ti-Chun Chan & Chien-Feng Li

  8. Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan

    Hong-Lin He

  9. Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

    Hong-Lin He, Wan-Shan Li & Chien-Feng Li

  10. Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Chien-Feng Li

Authors
  1. Tzu-Ju Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chia-Lin Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Feng Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cheng-Fa Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ti-Chun Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong-Lin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wan-Shan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hsin-Hwa Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chien-Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hong-Yue Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: C-FL, H-YL; methodology: T-JC, C-LC, Y-FT, C-FY, T-CC, H-LH, W-SL, H-HT; investigation: T-JC, C-LC, Y-FT, C-FY, T-CC, H-LH, W-SL, H-HT; formal analysis: T-JC, C-LC, Y-FT, C-FY, T-CC, H-LH, W-SL, H-HT; resources: H-LH, W-SL, H-HT; validation: T-JC, C-LC, Y-FT, C-FY, T-CC; visualization: T-JC, C-LC, Y-FT, C-FY, T-CC; writing—original draft: C-FL, H-YL; writing—review and editing: C-FL, H-YL; funding acquisition: C-FL, H-YL; supervision: C-FL, H-YL. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Chien-Feng Li or Hong-Yue Lai.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics approval and consent to participate

The study was approved by the Ethics Committee and Institutional Review Board of Chi Mei Medical Center (10302014) for the use of tumor samples disconnected from their identifiable information from the biobank following the ethical guidelines of the Helsinki Declaration and the regulations of our government.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 296 KB)

Supplementary file2 (DOCX 62 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, TJ., Chou, CL., Tian, YF. et al. High FRMD3 expression is prognostic for worse survival in rectal cancer patients treated with CCRT. Int J Clin Oncol 26, 1689–1697 (2021). https://doi.org/10.1007/s10147-021-01944-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-021-01944-6

Keywords

Search

Navigation