Skip to main content

Advertisement

SpringerLink
Log in

Long Non-coding RNA TPT1-AS1 Suppresses APC Transcription in a STAT1-Dependent Manner to Increase the Stemness of Colorectal Cancer Stem Cells

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Cancer stem cells (CSCs) are the major culprits leading to a new level of complexity and the consequential therapy resistance and disease recurrence in colorectal cancer (CRC). This study focuses on the effect of long non-coding RNA (lncRNA) TPT1-AS1 and its associated molecules on the stemness maintenance of CRC stem cells. TPT1-AS1 was identified as a significantly upregulated gene in CRC using the GSE146587 dataset. Stem cells from CRC HCT116 and CACO2 cells were isolated. TPT1-AS1 was significantly highly expressed in the CSCs compared to non-stem cells. Downregulation of TPT1-AS1 reduced the stemness of the CRC stem cells. TPT1-AS1 recruited STAT1 to the promoter region of APC to suppress APC transcription. Further upregulation of STAT1 or downregulation of APC blocked the role of TPT1-AS1 silencing and restored the malignant behaviors of CSC stem cells. APC inactivated the Wnt/β-catenin pathway. Overexpression of STAT1 restored the levels of cyclin D1 and β-catenin in cells suppressed by TPT1-AS1 silencing. In summary, this work demonstrates that TPT1-AS1 recruits STAT1 to suppress APC transcription and increase the stemness of colorectal CSCs via Wnt/β-catenin activation.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

The analyzed datasets generated during the study are available from the corresponding author on reasonable request.

Abbreviations

ANOVA:

Analysis of variance

APC:

Adenomatous polyposis coli

ChIP:

Chromatin immunoprecipitation

CSCs:

Cancer stem cells

DMEM:

Dulbecco's modified Eagle medium

FBS:

Fetal bovine serum

FISH:

Fluorescence in situ hybridization

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GEO:

Gene expression omnibus

HE:

Hematoxylin–eosin staining

HRP:

Horseradish peroxidase

IgG:

Immunoglobulin G

Mean ± SD:

Mean ± standard deviation

MT:

Mutant-type

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

RIP:

RNA immunoprecipitation

STAT1:

Signal transducer and activator of transcription 1

TCGA:

The cancer genome atlas

WT:

Wild-type

References

  1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi.org/10.3322/caac.21492

    Article  Google Scholar 

  2. Brody, H. (2015). Colorectal cancer. Nature, 521(7551), S1. https://doi.org/10.1038/521S1a

    Article  CAS  PubMed  Google Scholar 

  3. Simon, K. (2016). Colorectal cancer development and advances in screening. Clinical Interventions in Aging, 11, 967–976. https://doi.org/10.2147/CIA.S109285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Siegel, R. L., Miller, K. D., Fedewa, S. A., Ahnen, D. J., Meester, R. G. S., Barzi, A., & Jemal, A. (2017). Colorectal cancer statistics. CA: A Cancer Journal for Clinicians, 67(3), 177–193. https://doi.org/10.3322/caac.21395

    Article  Google Scholar 

  5. Munro, M. J., Wickremesekera, S. K., Peng, L., Tan, S. T., & Itinteang, T. (2018). Cancer stem cells in colorectal cancer: A review. Journal of Clinical Pathology, 71(2), 110–116. https://doi.org/10.1136/jclinpath-2017-204739

    Article  CAS  PubMed  Google Scholar 

  6. Zeuner, A., Todaro, M., Stassi, G., & De Maria, R. (2014). Colorectal cancer stem cells: From the crypt to the clinic. Cell Stem Cell, 15(6), 692–705. https://doi.org/10.1016/j.stem.2014.11.012

    Article  CAS  PubMed  Google Scholar 

  7. Lorenzi, L., Avila Cobos, F., Decock, A., Everaert, C., Helsmoortel, H., Lefever, S., Verboom, K., Volders, P. J., Speleman, F., Vandesompele, J., & Mestdagh, P. (2019). Long noncoding RNA expression profiling in cancer: Challenges and opportunities. Genes, Chromosomes & Cancer, 58(4), 191–199. https://doi.org/10.1002/gcc.22709

    Article  CAS  Google Scholar 

  8. Guo, Z., Zhou, C., Zhong, X., Shi, J., Wu, Z., Tang, K., Wang, Z., & Song, Y. (2019). The long noncoding RNA CTA-941F99 is frequently downregulated and may serve as a biomarker for carcinogenesis in colorectal cancer. J Clin Lab Anal. https://doi.org/10.1002/jcla.22986

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jiang, X., Zhu, Q., Wu, P., Zhou, F., & Chen, J. (2020). Upregulated long noncoding RNA LINC01234 predicts unfavorable prognosis for colorectal cancer and negatively correlates with KLF6 expression. Annals of Laboratory Medicine, 40(2), 155–163. https://doi.org/10.3343/alm.2020.40.2.155

    Article  CAS  PubMed  Google Scholar 

  10. Yan, H., & Bu, P. (2018). Non-coding RNAs in cancer stem cells. Cancer Letters, 421, 121–126. https://doi.org/10.1016/j.canlet.2018.01.027

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, Y., Sun, J., Qi, Y., Wang, Y., Ding, Y., Wang, K., Zhou, Q., Wang, J., Ma, F., Zhang, J., & Guo, B. (2020). Long non-coding RNA TPT1-AS1 promotes angiogenesis and metastasis of colorectal cancer through TPT1-AS1/NF90/VEGFA signaling pathway. Aging (Albany NY), 12(7), 6191–6205. https://doi.org/10.18632/aging.103016

    Article  CAS  Google Scholar 

  12. Long, Y., Wang, X., Youmans, D. T., & Cech, T. R. (2017). How do lncRNAs regulate transcription? Sci Adv. https://doi.org/10.1126/sciadv.aao2110

    Article  PubMed  PubMed Central  Google Scholar 

  13. Meng, C., Guo, L. B., Liu, X., Chang, Y. H., & Lin, Y. (2017). Targeting STAT1 in both cancer and insulin resistance diseases. Current Protein and Peptide Science, 18(2), 181–188. https://doi.org/10.2174/1389203718666161117114735

    Article  CAS  PubMed  Google Scholar 

  14. Wang, W., Zhang, L., Morlock, L., Williams, N. S., Shay, J. W., & De Brabander, J. K. (2019). Design and synthesis of TASIN analogues specifically targeting colorectal cancer cell lines with mutant adenomatous polyposis coli (APC). Journal of Medicinal Chemistry, 62(10), 5217–5241. https://doi.org/10.1021/acs.jmedchem.9b00532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Aghabozorgi, A. S., Bahreyni, A., Soleimani, A., Bahrami, A., Khazaei, M., Ferns, G. A., Avan, A., & Hassanian, S. M. (2019). Role of adenomatous polyposis coli (APC) gene mutations in the pathogenesis of colorectal cancer; current status and perspectives. Biochimie, 157, 64–71. https://doi.org/10.1016/j.biochi.2018.11.003

    Article  CAS  PubMed  Google Scholar 

  16. Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., & Shimono, Y. (2014). miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. eLife. https://doi.org/10.7554/eLife.01977

    Article  PubMed  PubMed Central  Google Scholar 

  17. Moradi, A., Pourseif, M. M., Jafari, B., Parvizpour, S., & Omidi, Y. (2020). Nanobody-based therapeutics against colorectal cancer: Precision therapies based on the personal mutanome profile and tumor neoantigens. Pharmacological Research, 156, 104790. https://doi.org/10.1016/j.phrs.2020.104790

    Article  CAS  PubMed  Google Scholar 

  18. Das, P. K., Islam, F., & Lam, A. K. (2020). The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells. https://doi.org/10.3390/cells9061392

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hu, C., Fang, K., Zhang, X., Guo, Z., & Li, L. (2020). Dyregulation of the lncRNA TPT1-AS1 positively regulates QKI expression and predicts a poor prognosis for patients with breast cancer. Pathology, Research and Practice, 216(11), 153216. https://doi.org/10.1016/j.prp.2020.153216

    Article  CAS  PubMed  Google Scholar 

  20. Gao, X., Cao, Y., Li, J., Wang, C., & He, H. (2020). LncRNA TPT1-AS1 sponges miR-23a-5p in glioblastoma to promote cancer cell proliferation. Cancer Biotherapy & Radiopharmaceuticals. https://doi.org/10.1089/cbr.2019.3484

    Article  Google Scholar 

  21. Wu, W., Gao, H., Li, X., Zhu, Y., Peng, S., Yu, J., Zhan, G., Wang, J., Liu, N., & Guo, X. (2019). LncRNA TPT1-AS1 promotes tumorigenesis and metastasis in epithelial ovarian cancer by inducing TPT1 expression. Cancer Science, 110(5), 1587–1598. https://doi.org/10.1111/cas.14009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Smillie, C. L., Sirey, T., & Ponting, C. P. (2018). Complexities of post-transcriptional regulation and the modeling of ceRNA crosstalk. Critical Reviews in Biochemistry and Molecular Biology, 53(3), 231–245. https://doi.org/10.1080/10409238.2018.1447542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Salmena, L., Poliseno, L., Tay, Y., Kats, L., & Pandolfi, P. P. (2011). A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell, 146(3), 353–358. https://doi.org/10.1016/j.cell.2011.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xu, H., Zhao, G., Zhang, Y., Jiang, H., Wang, W., Zhao, D., Yu, H., & Qi, L. (2019). Long non-coding RNA PAXIP1-AS1 facilitates cell invasion and angiogenesis of glioma by recruiting transcription factor ETS1 to upregulate KIF14 expression. Journal of Experimental & Clinical Cancer Research, 38(1), 486. https://doi.org/10.1186/s13046-019-1474-7

    Article  CAS  Google Scholar 

  25. Long, X., Song, K., Hu, H., Tian, Q., Wang, W., Dong, Q., Yin, X., & Di, W. (2019). Long non-coding RNA GAS5 inhibits DDP-resistance and tumor progression of epithelial ovarian cancer via GAS5-E2F4-PARP1-MAPK axis. Journal of Experimental & Clinical Cancer Research, 38(1), 345. https://doi.org/10.1186/s13046-019-1329-2

    Article  CAS  Google Scholar 

  26. Jiang, H., Li, T., Qu, Y., Wang, X., Li, B., Song, J., Sun, X., Tang, Y., Wan, J., Yu, Y., Zhan, J., & Zhang, H. (2018). Long non-coding RNA SNHG15 interacts with and stabilizes transcription factor Slug and promotes colon cancer progression. Cancer Letters, 425, 78–87. https://doi.org/10.1016/j.canlet.2018.03.038

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, Y., & Liu, Z. (2017). STAT1 in cancer: Friend or foe? Discovery Medicine, 24(130), 19–29.

    PubMed  Google Scholar 

  28. Liu, C., Shi, J., Li, Q., Li, Z., Lou, C., Zhao, Q., Zhu, Y., Zhan, F., Lian, J., Wang, B., Guan, X., Fang, L., Li, Z., Wang, Y., Zhou, B., Yao, Y., & Zhang, Y. (2019). STAT1-mediated inhibition of FOXM1 enhances gemcitabine sensitivity in pancreatic cancer. Clinical Science (London, England), 133(5), 645–663. https://doi.org/10.1042/CS20180816

    Article  CAS  Google Scholar 

  29. Tanaka, A., Zhou, Y., Ogawa, M., Shia, J., Klimstra, D. S., Wang, J. Y., & Roehrl, M. H. (2020). STAT1 as a potential prognosis marker for poor outcomes of early stage colorectal cancer with microsatellite instability. PLoS ONE, 15(4), e0229252. https://doi.org/10.1371/journal.pone.0229252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ji, D., Feng, Y., Peng, W., Li, J., Gu, Q., Zhang, Z., Qian, W., Wang, Q., Zhang, Y., & Sun, Y. (2020). NMI promotes cell proliferation through TGFbeta/Smad pathway by upregulating STAT1 in colorectal cancer. Journal of Cellular Physiology, 235(1), 429–441. https://doi.org/10.1002/jcp.28983

    Article  CAS  PubMed  Google Scholar 

  31. Sakahara, M., Okamoto, T., Oyanagi, J., Takano, H., Natsume, Y., Yamanaka, H., Kusama, D., Fusejima, M., Tanaka, N., Mori, S., Kawachi, H., Ueno, M., Sakai, Y., Noda, T., Nagayama, S., & Yao, R. (2019). IFN/STAT signaling controls tumorigenesis and the drug response in colorectal cancer. Cancer Science, 110(4), 1293–1305. https://doi.org/10.1111/cas.13964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang, Y., Guo, L., Li, Y., Feng, G. H., Teng, F., Li, W., & Zhou, Q. (2018). MicroRNA-494 promotes cancer progression and targets adenomatous polyposis coli in colorectal cancer. Molecular Cancer, 17(1), 1. https://doi.org/10.1186/s12943-017-0753-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Najafi, M., Farhood, B., & Mortezaee, K. (2019). Cancer stem cells (CSCs) in cancer progression and therapy. Journal of Cellular Physiology, 234(6), 8381–8395. https://doi.org/10.1002/jcp.27740

    Article  CAS  PubMed  Google Scholar 

  34. Nusse, R., & Varmus, H. (2012). Three decades of Wnts: A personal perspective on how a scientific field developed. EMBO Journal, 31(12), 2670–2684. https://doi.org/10.1038/emboj.2012.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Samowitz, W. S., Slattery, M. L., Sweeney, C., Herrick, J., Wolff, R. K., & Albertsen, H. (2007). APC mutations and other genetic and epigenetic changes in colon cancer. Molecular Cancer Research, 5(2), 165–170. https://doi.org/10.1158/1541-7786.MCR-06-0398

    Article  CAS  PubMed  Google Scholar 

  36. MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Developmental Cell, 17(1), 9–26. https://doi.org/10.1016/j.devcel.2009.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Project of Changzhou Medical Innovation Team (CCX201807).

Author information

Authors and Affiliations

  1. Department of General Surgery, Changzhou No. 2 People’s Hospital, No. 168, Gehu Road, Changzhou, 213100, Jiangsu, People’s Republic of China

    Bingxue Chen, Haojie Sun, Suting Xu & Qi Mo

Authors
  1. Bingxue Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haojie Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suting Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BXC is the guarantor of integrity of the entire study and contributed to the concepts; BXC, HJS, STX, and QM contributed to the data acquisition and statistical analysis; BXC contributed to the experimental studies; BXC and HJS contributed to the manuscript preparation. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qi Mo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All animal experiments were approved by the Animal Ethical Committee of Changzhou No. 2 People’s Hospital and strictly performed in accordance with the National Institutes of Health Guide to the Care and Use of Laboratory Animals (8th edition, 2011).

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, B., Sun, H., Xu, S. et al. Long Non-coding RNA TPT1-AS1 Suppresses APC Transcription in a STAT1-Dependent Manner to Increase the Stemness of Colorectal Cancer Stem Cells. Mol Biotechnol 64, 560–574 (2022). https://doi.org/10.1007/s12033-022-00448-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-022-00448-6

Keywords

Search

Navigation