Cargando…

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

BACKGROUND: Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients' surv...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Hao, Zhang, Zhenzhan, Zhen, Peilin, Zhou, Meijuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811563/
https://www.ncbi.nlm.nih.gov/pubmed/33506057
http://dx.doi.org/10.1155/2021/6657012
_version_ 1783637527657185280
author Liu, Hao
Zhang, Zhenzhan
Zhen, Peilin
Zhou, Meijuan
author_facet Liu, Hao
Zhang, Zhenzhan
Zhen, Peilin
Zhou, Meijuan
author_sort Liu, Hao
collection PubMed
description BACKGROUND: Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients' survival prognosis. The resistance to chemoradiotherapy in rectal cancer is difficult to predict. This study was aimed at evaluating the role of V-set and transmembrane domain containing 2 like protein (VSTM2L) in resistance to chemoradiotherapy in rectal cancer. METHODS: Analysis of the GEO profiling datasets of rectal cancer patients receiving pCRT disclosed that VSTM2L as a candidate gene was significantly upregulated in nonresponders of rectal cancer with pCRT. The mRNA and protein expression of VSTM2L was detected by quantitate real-time PCR, western blotting, and immunohistochemistry in six rectal cancer biopsy tissues before pCRT. Furthermore, the rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. Overexpression of VSTM2L in cancer cells treated with CRT was analyzed for the function of cell proliferation and viability, clone formation, DNA damage repair, and apoptosis ability. The GSEA and RNA-sequence analysis were used to find the downstream mechanism of VSTM2L overexpression in cells treated with CRT. RESULTS: The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. High expression of VSTM2L was significantly associated with tumor regression after pCRT (P = 0.030). Moreover, high expression of VSTM2L reduced γ-H2AX expression in rectal cancer patient-derived organoids treated with CRT. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The molecular mechanism revealed that the overexpression of VSTM2L induced resistance to CRT through downstream IL-4 signaling affecting the progress of cell proliferation and apoptosis. CONCLUSION: The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT.
format Online
Article
Text
id pubmed-7811563
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-78115632021-01-26 High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling Liu, Hao Zhang, Zhenzhan Zhen, Peilin Zhou, Meijuan J Immunol Res Research Article BACKGROUND: Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients' survival prognosis. The resistance to chemoradiotherapy in rectal cancer is difficult to predict. This study was aimed at evaluating the role of V-set and transmembrane domain containing 2 like protein (VSTM2L) in resistance to chemoradiotherapy in rectal cancer. METHODS: Analysis of the GEO profiling datasets of rectal cancer patients receiving pCRT disclosed that VSTM2L as a candidate gene was significantly upregulated in nonresponders of rectal cancer with pCRT. The mRNA and protein expression of VSTM2L was detected by quantitate real-time PCR, western blotting, and immunohistochemistry in six rectal cancer biopsy tissues before pCRT. Furthermore, the rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. Overexpression of VSTM2L in cancer cells treated with CRT was analyzed for the function of cell proliferation and viability, clone formation, DNA damage repair, and apoptosis ability. The GSEA and RNA-sequence analysis were used to find the downstream mechanism of VSTM2L overexpression in cells treated with CRT. RESULTS: The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. High expression of VSTM2L was significantly associated with tumor regression after pCRT (P = 0.030). Moreover, high expression of VSTM2L reduced γ-H2AX expression in rectal cancer patient-derived organoids treated with CRT. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The molecular mechanism revealed that the overexpression of VSTM2L induced resistance to CRT through downstream IL-4 signaling affecting the progress of cell proliferation and apoptosis. CONCLUSION: The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT. Hindawi 2021-01-08 /pmc/articles/PMC7811563/ /pubmed/33506057 http://dx.doi.org/10.1155/2021/6657012 Text en Copyright © 2021 Hao Liu et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Liu, Hao
Zhang, Zhenzhan
Zhen, Peilin
Zhou, Meijuan
High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling
title High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling
title_full High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling
title_fullStr High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling
title_full_unstemmed High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling
title_short High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling
title_sort high expression of vstm2l induced resistance to chemoradiotherapy in rectal cancer through downstream il-4 signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811563/
https://www.ncbi.nlm.nih.gov/pubmed/33506057
http://dx.doi.org/10.1155/2021/6657012
work_keys_str_mv AT liuhao highexpressionofvstm2linducedresistancetochemoradiotherapyinrectalcancerthroughdownstreamil4signaling
AT zhangzhenzhan highexpressionofvstm2linducedresistancetochemoradiotherapyinrectalcancerthroughdownstreamil4signaling
AT zhenpeilin highexpressionofvstm2linducedresistancetochemoradiotherapyinrectalcancerthroughdownstreamil4signaling
AT zhoumeijuan highexpressionofvstm2linducedresistancetochemoradiotherapyinrectalcancerthroughdownstreamil4signaling