Evidence map›Paper›PMID 39739077›Full record

ArticleMolecular biomedicine2024

Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma.

Xiaolu Ma, Kaixia Zhou, Tianqing Yan, Ling Hu, Suhong Xie, Hui Zheng, Ying Tong, Heng Zhang, Yanchun Wang, Zhiyun Gong and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular biomedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Xiaolu Ma *Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Kaixia Zhou *Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Tianqing Yan *Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Ling Hu *Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Suhong XieDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Hui ZhengDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Ying TongDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Heng ZhangDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Yanchun WangDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Zhiyun GongDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Cuncun ChenDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Yanan TianDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Lin GuoDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. Guolin500@hotmail.com.
Renquan LuDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.ORCID 0000-0003-3291-5742

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Lenvatinib, an approved first-line regimen, has been widely applied in hepatocellular carcinoma (HCC). However, clinical response towards Lenvatinib was limited, emphasizing the importance of understanding the underlying mechanism of its resistance. Herein, we employed integrated bioinformatic analysis to identify calpain-2 (CAPN2) as a novel key regulator for Lenvatinib resistance in HCC, and its expression greatly increased in both Lenvatinib-resistant HCC cell lines and clinical samples. Further in vitro and in vivo experiments indicated that knocking down CAPN2 greatly sensitized HCC cells to Lenvatinib treatment, while overexpression of CAPN2 achieved opposite effects in a Lenvatinib-sensitive HCC cell line. Interestingly, we observed a close relationship between CAPN2 expression and cancer stem cell (CSC) traits in HCC cells, evidenced by impaired sphere-forming and CSC-related marker expressions after CAPN2 knockdown, and verse vice. Mechanistically, we strikingly discovered that CAPN2 exerted its function by both enzyme-dependent and enzyme-independent manner simultaneously: activating β-Catenin signaling through its enzyme activity, and preventing GLI1/GLI2 degradation through direct binding to YWHAE in an enzyme-independent manner, which disrupting the association between YWHAE and GLI1/GLI2 to inhibit YWHAE-induced degradation of GLIs. Notably, further co-immunoprecipitation assays revealed that YWHAE could promote the protein stability of CAPN2 via recruiting a deubiquitinase COPS5 to prevent ubiquitination-induced degradation of CAPN2. In summary, our data demonstrated that CAPN2 promoted Lenvatinib resistance via both catalytic activity-dependent and -independent approaches. Reducing CAPN2 protein rather than inhibiting its activity might be a promising strategy to improve Lenvatinib treatment efficiency in HCC.

Indexed as

CalpainCarcinoma, HepatocellularDrug Resistance, NeoplasmLiver NeoplasmsNeoplastic Stem CellsPhenylurea CompoundsProteolysisQuinolinesAnimalsAntineoplastic AgentsCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceAntineoplastic AgentsCalpainCAPN2 protein, humanlenvatinibPhenylurea CompoundsQuinolines

Identifiers

PMID39739077
PMCPMC11688263

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.