LncRNA HCG18 Suppresses CD8⁺ T Cells to Confer Resistance to Cetuximab in Colorectal Cancer Via miR-20b-5p/PD-L1 Axis

Abstract

Aim: We aimed to explore the effect of long noncoding RNA HCG18 in colorectal cancer (CRC). Materials & methods: Relative gene and protein expression were screened. Colony formation and flow cytometry assays were performed to determine proliferation and apoptosis. Dual luciferase and RNA immunoprecipitation assays were conducted to validate the interaction between indicated molecules. Xenograft in nude mice was applied to verify the conclusion in vivo. Results:HCG18 and PD-L1 were upregulated while miR-20b-5p was downregulated in CRC tissue. Functional analysis revealed that lncRNA HCG18 promoted proliferation, migration and resistance to cetuximab of CRC cells via the miR-20b-5p/PD-L1 axis. Conclusion:HCG18 facilitated progress of the tumor, conferred to cetuximab resistance and suppressed CD8⁺ T cells via the miR-20b-5p/PD-L1 axis.

Graphical abstract

Lay abstract

In the present study, we found a long noncoding RNA (lncRNA), HCG18 (a recently discovered lncRNA that facilitates tumor progression via multiple mechanisms), was upregulated in colorectal cancer (CRC). Further studies revealed that HCG18 suppressed CD8⁺ T-cell (cytotoxic T lymphocyte which kills cancer cell) activation to induce cetuximab (a first-line drug in CRC) resistance. Mechanically, HCG18 elevated expression of PD-L1 (a receptor in T-cell membranes, thus suppressing the proliferation of CD8⁺ cytotoxic T lymphocytes) via sponging (lncRNA binds with miRNA) miR-20b-5p. This study might provide a deeper insight into understanding cetuximab resistance in CRC.

Keywords: :

• CD8⁺ T cell
• cetuximab
• colorectal cancer
• lncRNA HCG18
• miR-20b-5p
• PD-L1

Author contributions

Y-J Xu: experimental studies, data analysis, preparation and editing; J-M Zhao: data acquisition; X-F Ni: data analysis; W Wang: experimental studies; W-W Hu: experimental studies and review; C-P Wu: supervision, concepts and design; all the authors approved for the final version.

Financial & competing interests disclosure

This work was supported by Youth Talent Science and Technology Project of Changzhou Health and Technology Commission (QN201803), Changzhou Youth Talent Project (CZQM2020033) and Medical Innovation Team Project of Jiangsu Province (2017–1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. This study was approved by ethics committee of the Third Affiliated Hospital of Soochow University. Signed written informed consents were obtained before samples were collected. All animal experiments and protocols have been reviewed and approved by the Animal Care and Use Committee of the Third Affiliated Hospital of Soochow University.

Data sharing statement

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by Youth Talent Science and Technology Project of Changzhou Health and Technology Commission (QN201803), Changzhou Youth Talent Project (CZQM2020033) and Medical Innovation Team Project of Jiangsu Province (2017–1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.