Skip to content
2000
image of SLC41A2 Suppresses Colon Cancer Progression by Inhibiting GSK3β Ubiquitin-proteasome Degradation

Abstract

Background

Colon cancer is a highly prevalent tumor with a high mortality rate worldwide. SLC41A2 is a member of the solute carrier family, but its role in colon cancer is still unclear.

Methods

The relationship between the expression level of SLC41A2 and clinicopathological features in colon cancer was investigated using data from the TCGA database. The differential expression genes of SLC41A2 were identified the potential role of SLC41A2 in colon cancer was analysed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. By transfecting plasmids or siRNA to overexpress or knock down SLC41A2 in colon cancer cells, the effects of SLC41A2 on colon cancer cell proliferation, migration, and apoptosis were detected through EdU, MTT, wound-healing, Transwell, and JC-1 experiments. Western blot and ubiquitination experiments validated the regulation of GSK3β stability by SLC41A2. Rescue experiments and CCK8 assays confirmed the regulatory effect of SLC41A2 on GSK3β.

Results

Compared to normal tissues, SLC41A2 exhibited a lower expression level in colon cancer, and the expression levels of SLC41A2 were correlated with the stage and Tumor Node Metastasis (TNM) classification. GO and KEGG analyses displayed that SLC41A2 primarily affected the growth factor activity and Wnt signaling pathway. Furthermore, elevated expression of SLC41A2 notably decreased the proliferation, migration and invasion of colon cancer cells, along with increased apoptosis. The overexpression of SLC41A2 and rescue experiments confirmed that SLC41A2 enhances the protein stability of GSK3β by inhibiting its ubiquitin-proteasome degradation and causes the upregulation of GSK3β, thereby suppressing the progression of colon cancer.

Conclusion

SLC41A2 was lowly expressed in colon cancer tissues or cells. By inhibiting the ubiquitin-proteasome degradation of GSK3β, SLC41A2 can significantly upregulate the expression of GSK3β, which ultimately suppresses the proliferation and migration of colon cancer cells.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240397574250630060947
2025-07-07
2025-09-14

  • From This Site

    /content/journals/cmm/10.2174/0115665240397574250630060947
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Siegel R.L. Kratzer T.B. Giaquinto A.N. Sung H. Jemal A. Cancer statistics, 2025. CA Cancer J. Clin. 2025 75 1 10 45 10.3322/caac.21871 39817679
    [Google Scholar]
  2. Siegel R.L. Wagle N.S. Cercek A. Smith R.A. Jemal A. Colorectal cancer statistics, 2023. CA Cancer J. Clin. 2023 73 3 233 254 10.3322/caac.21772 36856579
    [Google Scholar]
  3. Lin L. Yee S.W. Kim R.B. Giacomini K.M. SLC transporters as therapeutic targets: Emerging opportunities. Nat. Rev. Drug Discov. 2015 14 8 543 560 10.1038/nrd4626 26111766
    [Google Scholar]
  4. Fu Y. Chen J. Zhu X. Ding M. Wang H. Fu S. Roles and therapeutic potential of the SLC family in prostate cancer—literature review. BMC Urol. 2025 25 1 32 10.1186/s12894‑025‑01714‑w 39966814
    [Google Scholar]
  5. Xiong L. Luo Y. Yuan T. Lin W. Lin B. Wu C. Prognostic 7-SLC-gene signature identified via weighted gene co-expression network analysis for patients with hepatocellular carcinoma. J. Oncol. 2023 2023 1 4364654 10.1155/2023/4364654
    [Google Scholar]
  6. Yu T. Yu S. Lu K. Comprehensive molecular analyses of an SLC family-based model in stomach adenocarcinoma. Pathol. Oncol. Res. 2022 28 1610610 10.3389/pore.2022.1610610 36313898
    [Google Scholar]
  7. Stary D. Bajda M. Structural studies of the taurine transporter: A potential biological target from the GABA transporter subfamily in cancer therapy. Int. J. Mol. Sci. 2024 25 13 7339 10.3390/ijms25137339 39000444
    [Google Scholar]
  8. Song H.S. Ha S.Y. Kim J.Y. Kim M. Choi J.H. The effect of genetic variants of SLC22A18 on proliferation, migration, and invasion of colon cancer cells. Sci. Rep. 2024 14 1 3925 10.1038/s41598‑024‑54658‑w 38366023
    [Google Scholar]
  9. Nemoto T. Tagashira H. Kita T. Kita S. Iwamoto T. Functional characteristics and therapeutic potential of SLC41 transporters. J. Pharmacol. Sci. 2023 151 2 88 92 10.1016/j.jphs.2022.12.003 36707183
    [Google Scholar]
  10. Sahni J. Scharenberg A.M. The SLC41 family of MgtE-like magnesium transporters. Mol. Aspects Med. 2013 34 2-3 620 628 10.1016/j.mam.2012.05.012 23506895
    [Google Scholar]
  11. Zhao H. Ming T. Tang S. Wnt signaling in colorectal cancer: Pathogenic role and therapeutic target. Mol. Cancer 2022 21 1 144 10.1186/s12943‑022‑01616‑7 35836256
    [Google Scholar]
  12. Song P. Gao Z. Bao Y. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J. Hematol. Oncol. 2024 17 1 46 10.1186/s13045‑024‑01563‑4 38886806
    [Google Scholar]
  13. Albrecht L.V. Tejeda-Muñoz N. De Robertis E.M. Cell biology of canonical wnt signaling. Annu. Rev. Cell Dev. Biol. 2021 37 1 369 389 10.1146/annurev‑cellbio‑120319‑023657 34196570
    [Google Scholar]
  14. Kim W.K. Kwon Y. Jang M. β-catenin activation down-regulates cell-cell junction-related genes and induces epithelial-to-mesenchymal transition in colorectal cancers. Sci. Rep. 2019 9 1 18440 10.1038/s41598‑019‑54890‑9 31804558
    [Google Scholar]
  15. Ritchie M.E. Phipson B. Wu D. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015 43 7 47 10.1093/nar/gkv007 25605792
    [Google Scholar]
  16. Yu G. Wang L.G. Han Y. He Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012 16 5 284 287 10.1089/omi.2011.0118 22455463
    [Google Scholar]
  17. Ito K. Murphy D. Application of ggplot2 to pharmacometric graphics. CPT Pharmacometrics Syst. Pharmacol. 2013 2 10 1 16 10.1038/psp.2013.56 24132163
    [Google Scholar]
  18. Zeng C. Qi G. Shen Y. DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2. Cancer Med. 2023 12 1 412 424 10.1002/cam4.4926 35670012
    [Google Scholar]
  19. Gou Q. Chen H. Chen M. Inhibition of CK2/ING4 pathway facilitates non‐small cell lung cancer immunotherapy. Adv. Sci. 2023 10 34 2304068 10.1002/advs.202304068 37870169
    [Google Scholar]
  20. Dai Y. Liu J. Li X. Let‐7b‐5p inhibits colon cancer progression by prohibiting APC ubiquitination degradation and the Wnt pathway by targeting NKD1. Cancer Sci. 2023 114 5 1882 1897 10.1111/cas.15678 36445120
    [Google Scholar]
  21. Wang Y. Yang C. Li W. Identification of colon tumor marker NKD1 via integrated bioinformatics analysis and experimental validation. Cancer Med. 2021 10 20 7383 7394 10.1002/cam4.4224 34547189
    [Google Scholar]
  22. Sarkar J. Das M. Howlader M.S.I. Prateeksha P. Barthels D. Das H. Epigallocatechin-3-gallate inhibits osteoclastic differentiation by modulating mitophagy and mitochondrial functions. Cell Death Dis. 2022 13 10 908 10.1038/s41419‑022‑05343‑1 36307395
    [Google Scholar]
  23. Liu Q. Deng J. Yang C. DPEP1 promotes the proliferation of colon cancer cells via the DPEP1/MYC feedback loop regulation. Biochem. Biophys. Res. Commun. 2020 532 4 520 527 10.1016/j.bbrc.2020.08.063 32896379
    [Google Scholar]
  24. Pastushenko I. Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019 29 3 212 226 10.1016/j.tcb.2018.12.001 30594349
    [Google Scholar]
  25. Balamurugan K. Poria D.K. Sehareen S.W. Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight 2023 8 6 156057 10.1172/jci.insight.156057 36757813
    [Google Scholar]
  26. Zhou L. Jiang J. Huang Z. Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA. Mol. Cancer 2022 21 1 168 10.1186/s12943‑022‑01638‑1 35986274
    [Google Scholar]
  27. Xue W. Yang L. Chen C. Ashrafizadeh M. Tian Y. Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell. Mol. Life Sci. 2024 81 1 79 10.1007/s00018‑023‑05099‑7 38334836
    [Google Scholar]
  28. Chen H.C. Su L.T. González-Pagán O. Overton J.D. Runnels L.W. A key role for Mg2+ in TRPM7's control of ROS levels during cell stress. Biochem. J. 2012 445 3 441 448 10.1042/BJ20120248 22587440
    [Google Scholar]
  29. Kieboom B.C.T. Ligthart S. Dehghan A. Serum magnesium and the risk of prediabetes: A population-based cohort study. Diabetologia 2017 60 5 843 853 10.1007/s00125‑017‑4224‑4 28224192
    [Google Scholar]
  30. Ramakrishnan K. Vishwakarma R. Dev R.R. Raju R. Rehman N. Etiologically significant microRNAs in hepatitis B virus-induced hepatocellular carcinoma. OMICS 2024 28 6 280 290 10.1089/omi.2024.0071 38818956
    [Google Scholar]
  31. Zhang Y.J. Zhang L. Feng F. Cao Q.F. ANGPTL3 overexpression suppresses the development of oncogenic properties in renal cell carcinoma via the Wnt/β-catenin signaling pathway and predicts good prognosis. Dis. Markers 2021 2021 2863856 10.1155/2021/2863856
    [Google Scholar]
  32. Yi J. Ren L. Li D. Trefoil factor 1 (TFF1) is a potential prognostic biomarker with functional significance in breast cancers. Biomed. Pharmacother. 2020 124 109827 10.1016/j.biopha.2020.109827 31986408
    [Google Scholar]
  33. Jin Y. Cai Q. Wang L. Paracrine activin B-NF-κB signaling shapes an inflammatory tumor microenvironment in gastric cancer via fibroblast reprogramming. J. Exp. Clin. Cancer Res. 2023 42 1 269 10.1186/s13046‑023‑02861‑4 37858201
    [Google Scholar]
  34. Zhang J. Chen B. Li H. Cancer‐associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2 – IGF1R and Hippo–YAP1 signaling pathways. J. Pathol. 2023 259 2 205 219 10.1002/path.6033 36373776
    [Google Scholar]
  35. Chen L. Zhang X. Liu G. Fibroblast growth factor 3 promotes spontaneous mammary tumorigenesis in Tientsin albino 2 mice via the FGF3/FGFR1/STAT3 pathway. Front. Oncol. 2023 13 1161410 10.3389/fonc.2023.1161410 37496658
    [Google Scholar]
  36. Fujiya K. Ohshima K. Kitagawa Y. Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors. Eur. J. Surg. Oncol. 2020 46 6 1080 1087 10.1016/j.ejso.2020.02.036 32147424
    [Google Scholar]
  37. Park S. Cui J. Yu W. Wu L. Carmon K.S. Liu Q.J. Differential activities and mechanisms of the four R-spondins in potentiating Wnt/β-catenin signaling. J. Biol. Chem. 2018 293 25 9759 9769 10.1074/jbc.RA118.002743 29752411
    [Google Scholar]
  38. Wang J. Yu H. Dong W. N6-methyladenosine–mediated up-regulation of FZD10 regulates liver cancer stem cells’ properties and lenvatinib resistance through WNT/β-catenin and hippo signaling pathways. Gastroenterology 2023 164 6 990 1005 10.1053/j.gastro.2023.01.041 36764493
    [Google Scholar]
  39. Zacarías-Fluck M.F. Jauset T. Martínez-Martín S. The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets. Life Sci. Alliance 2021 4 5 201900490 10.26508/lsa.201900490 33653688
    [Google Scholar]
  40. Maurice M.M. Angers S. Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction. Nat. Rev. Mol. Cell Biol. 2025 26 5 371 388 10.1038/s41580‑024‑00823‑y 39856369
    [Google Scholar]
  41. Fontana R. Mestre-Farrera A. Yang J. Update on epithelial-mesenchymal plasticity in cancer progression. Annu. Rev. Pathol. 2024 19 1 133 156 10.1146/annurev‑pathmechdis‑051222‑122423 37758242
    [Google Scholar]
  42. Babaei G. Aziz S.G.G. Jaghi N.Z.Z. EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomed. Pharmacother. 2021 133 110909 10.1016/j.biopha.2020.110909 33227701
    [Google Scholar]
  43. Khan A.Q. Hasan A. Mir S.S. Rashid K. Uddin S. Steinhoff M. Exploiting transcription factors to target EMT and cancer stem cells for tumor modulation and therapy. Semin. Cancer Biol. 2024 100 1 16 10.1016/j.semcancer.2024.03.002 38503384
    [Google Scholar]
  44. Qin K. Yu M. Fan J. Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk. Genes Dis. 2024 11 1 103 134 10.1016/j.gendis.2023.01.030 37588235
    [Google Scholar]
  45. Lin J. Song T. Li C. Mao W. GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer. Biochim. Biophys. Acta Mol. Cell Res. 2020 1867 5 118659 10.1016/j.bbamcr.2020.118659
    [Google Scholar]
  46. Gong R.H. Chen M. Huang C. Wong H.L.X. Kwan H.Y. Bian Z. Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin–proteasome pathway. Cell Commun. Signal. 2022 20 1 34 10.1186/s12964‑022‑00834‑2 35305671
    [Google Scholar]
  47. Gao X. You J. Gong Y. WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit. Acta Pharm. Sin. B 2022 12 3 1225 1239 10.1016/j.apsb.2021.10.021 35530152
    [Google Scholar]
  48. Yusufova N. Kloetgen A. Teater M. Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture. Nature 2021 589 7841 299 305 10.1038/s41586‑020‑3017‑y 33299181
    [Google Scholar]
  49. Kalra R. Bhagyaraj E. Tiwari D. AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment. Oncogenesis 2018 7 5 43 10.1038/s41389‑018‑0053‑7 29795364
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240397574250630060947
Loading
SLC41A2 Suppresses Colon Cancer Progression by Inhibiting GSK3β Ubiquitin-proteasome Degradation
Bentham Science Publishers ; https://doi.org/10.2174/0115665240397574250630060947
/content/journals/cmm/10.2174/0115665240397574250630060947
/content/journals/cmm/10.2174/0115665240397574250630060947
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: Colon cancer ; metastasis ; GSK3β ; proliferation ; SLC41A2 ; Wnt signaling pathway

Most Cited Most Cited RSS feed

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