B7-H3 regulates KIF15-activated ERK1/2 pathway and contributes to radioresistance in colorectal cancer.
Apoptosis
/ genetics
B7 Antigens
/ genetics
Cell Line, Tumor
Colonic Neoplasms
/ genetics
Colorectal Neoplasms
/ genetics
Drug Resistance, Neoplasm
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Kinesins
/ genetics
MAP Kinase Signaling System
/ genetics
RNA, Small Interfering
/ genetics
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
03 10 2020
03 10 2020
Historique:
received:
09
06
2020
accepted:
23
09
2020
revised:
21
09
2020
entrez:
4
10
2020
pubmed:
5
10
2020
medline:
14
5
2021
Statut:
epublish
Résumé
As an important modality for the local control of colorectal cancer (CRC), radiotherapy or neoadjuvant radiotherapy is widely applied in the clinic, but radioresistance has become a major obstacle for CRC radiotherapy. Here we reported that B7-H3, an important costimulatory molecule, is associated with radioresistance in CRC. The expression of B7-H3 was obviously increased in CRC cells after irradiation. The enhanced expression of B7-H3 promoted, while the knockdown of B7-H3 inhibited, colony formation and cell activity in CRC cells following radiation treatment. B7-H3 overexpression reduced S phase arrest and protected cell apoptosis induced by radiation, whereas B7-H3 knockdown had the opposite effects. In addition, B7-H3 blockade by 3E8, a specific B7-H3 antibody, significantly sensitized CRC cells to irradiation in vivo. Mechanistic analysis revealed that B7-H3 regulated KIF15 via RNA sequencing, which was in dependent of NF-κB pathway. And small interfering RNA (siRNA)-mediated KIF15 silencing or KIF15 blockade by the inhibitor SB743921 abolished the effect of B7-H3 on radioresistance in vitro and in vivo. Similar to B7-H3, we find that the protein expression levels of KIF15, which showed a positive correlation with B7-H3, was abnormal upregulated in cancer tissues than in adjacent normal tissues and associated with TNM stage. Finally, B7-H3/KIF15 enhanced resistance against irradiation in CRC cells via activating ERK1/2 signaling, a key pathway involved in radioresistance in cancer. Our findings reveal an alternative mechanism by which CRC cells can acquire radioresistance via the B7-H3/KIF15/ERK axis.
Identifiants
pubmed: 33011740
doi: 10.1038/s41419-020-03041-4
pii: 10.1038/s41419-020-03041-4
pmc: PMC7532977
doi:
Substances chimiques
B7 Antigens
0
CD276 protein, human
0
KIF15 protein, human
0
RNA, Small Interfering
0
Kinesins
EC 3.6.4.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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