TY - JOUR
T1 - SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression
AU - Nakano, Yusuke
AU - Masuda, Takaaki
AU - Sakamoto, Takeharu
AU - Tanaka, Noritaka
AU - Tobo, Taro
AU - Hashimoto, Masahiro
AU - Tatsumi, Takanari
AU - Saito, Hideyuki
AU - Takahashi, Junichi
AU - Koike, Kensuke
AU - Abe, Tadashi
AU - Ando, Yuki
AU - Ozato, Yuki
AU - Hosoda, Kiyotaka
AU - Hirose, Kosuke
AU - Higuchi, Satoshi
AU - Ikehara, Tomohiko
AU - Hisamatsu, Yuichi
AU - Toshima, Takeo
AU - Yonemura, Yusuke
AU - Ogino, Takayuki
AU - Uemura, Mamoru
AU - Eguchi, Hidetoshi
AU - Doki, Yuichiro
AU - Mimori, Koshi
N1 - Publisher Copyright:
Copyright © 2024 Nakano et al.
PY - 2024/12
Y1 - 2024/12
N2 - Colorectal cancer (CRC) is widely prevalent and represents a significant contributor to global cancer‑related mortality. There remains a pressing demand for advance‑ ments in CRC treatment modalities. The E3 ubiquitin ligase is a critical enzyme involved in modulating protein expression levels via posttranslational ubiquitin‑mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In the present study, using comprehensive expression analysis involving spatial transcriptomic analysis with single‑cell RNA sequencing in clinical CRC datasets, the ubiquitin‑associated protein Shank‑associated RH domain interactor (SHARPIN) was identified, located on amplified chromosome 8q, which could promote CRC progression. SHARPIN was found to be upregulated in tumor cells, with elevated expression observed in tumor tissues. This heightened expression of SHARPIN was positively associated with lymphatic invasion and served as an independent predictor of a poor prognosis in patients with CRC. In vitro and in vivo analyses using SHARPIN‑overexpressing or ‑knockout CRC cells revealed that SHARPIN overexpression upregulated MDM2, resulting in the downregulation of p53, while SHARPIN silencing or knockout downregulated MDM2, leading to p53 upregulation, which affects cell cycle progression, tumor cell apoptosis and tumor growth in CRC. Furthermore, SHARPIN was found to be overexpressed in several cancer types, exerting significant effects on survival outcomes. In conclusion, SHARPIN represents a newly identified novel gene with the potential to promote tumor growth following apoptosis inhibition and cell cycle progression in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.
AB - Colorectal cancer (CRC) is widely prevalent and represents a significant contributor to global cancer‑related mortality. There remains a pressing demand for advance‑ ments in CRC treatment modalities. The E3 ubiquitin ligase is a critical enzyme involved in modulating protein expression levels via posttranslational ubiquitin‑mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In the present study, using comprehensive expression analysis involving spatial transcriptomic analysis with single‑cell RNA sequencing in clinical CRC datasets, the ubiquitin‑associated protein Shank‑associated RH domain interactor (SHARPIN) was identified, located on amplified chromosome 8q, which could promote CRC progression. SHARPIN was found to be upregulated in tumor cells, with elevated expression observed in tumor tissues. This heightened expression of SHARPIN was positively associated with lymphatic invasion and served as an independent predictor of a poor prognosis in patients with CRC. In vitro and in vivo analyses using SHARPIN‑overexpressing or ‑knockout CRC cells revealed that SHARPIN overexpression upregulated MDM2, resulting in the downregulation of p53, while SHARPIN silencing or knockout downregulated MDM2, leading to p53 upregulation, which affects cell cycle progression, tumor cell apoptosis and tumor growth in CRC. Furthermore, SHARPIN was found to be overexpressed in several cancer types, exerting significant effects on survival outcomes. In conclusion, SHARPIN represents a newly identified novel gene with the potential to promote tumor growth following apoptosis inhibition and cell cycle progression in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.
KW - colorectal cancer
KW - novel gene
KW - p53
KW - shank‑associated RH domain interactor
KW - ubiquitin‑proteasome system
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U2 - 10.3892/ijo.2024.5701
DO - 10.3892/ijo.2024.5701
M3 - Article
C2 - 39450547
AN - SCOPUS:85207354330
SN - 1019-6439
VL - 65
JO - International journal of oncology
JF - International journal of oncology
IS - 6
M1 - 113
ER -