Dataset Information

SPINK4 promotes colorectal cancer cell proliferation and inhibits ferroptosis.

ABSTRACT:

Background

Little is known about the role of serine peptidase inhibitor Kazal type 4 (SPINK4) in colorectal cancer (CRC) and ferroptosis. Therefore, this study aimed to determine the effect of SPINK4 on CRC pathogenesis and ferroptosis.

Methods

SPINK4 expression was analyzed in public datasets and examined using immunohistochemistry. The biological function of SPINK4 in CRC cell lines and its effect on ferroptosis were tested. An immunofluorescence assay was performed to determine the location of SPINK4 in cells, and mouse models were established to determine the effects of SPINK4 in vivo.

Results

CRC datasets and clinical samples analysis revealed that SPINK4 mRNA and protein levels were significantly reduced in CRC tissues compared to control tissues (P < 0.05). Two CRC cell lines (HCT116 and LoVo) were selected, and the in vitro and in vivo experiments showed that overexpression of SPINK4 greatly promotes the proliferation and metastasis of CRC cells and tumor growth (P < 0.05). The immunofluorescence assay indicated that SPINK4 is mainly located in the nucleoplasm and nucleus of CRC cells. Furthermore, SPINK4 expression was reduced after cell ferroptosis induced by Erastin, and overexpression of SPINK4 greatly inhibited ferroptosis in CRC cells. The results of mouse model further demonstrated that SPINK4 overexpression inhibited CRC cell ferroptosis and facilitated tumor growth.

Conclusions

SPINK4 was decreased in CRC tissues and promoted cell proliferation and metastasis; overexpression of SPINK4 inhibited CRC cell ferroptosis.

SUBMITTER: Hu BL

PROVIDER: S-EPMC10071753 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

SPINK4 promotes colorectal cancer cell proliferation and inhibits ferroptosis.

Hu Bang-Li BL Yin Yi-Xin YX Li Ke-Zhi KZ Li Si-Qi SQ Li Zhao Z

BMC gastroenterology 20230403 1

<h4>Background</h4>Little is known about the role of serine peptidase inhibitor Kazal type 4 (SPINK4) in colorectal cancer (CRC) and ferroptosis. Therefore, this study aimed to determine the effect of SPINK4 on CRC pathogenesis and ferroptosis.<h4>Methods</h4>SPINK4 expression was analyzed in public datasets and examined using immunohistochemistry. The biological function of SPINK4 in CRC cell lines and its effect on ferroptosis were tested. An immunofluorescence assay was performed to determine ...[more]

PMID: 37013514

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Project description:BackgroundColorectal cancer (CRC) is one of the most common malignancies and is characterized by reprogrammed metabolism. Ferroptosis, a programmed cell death dependent on iron, has emerged as a promising strategy for CRC treatment. Although small nucleolar RNAs are extensively involved in carcinogenesis, it is unclear if they regulate ferroptosis during CRC pathogenesis.MethodsThe dysregulated snoRNAs were identified using published sequencing data of CRC tissues. The expression of the candidate snoRNAs, host gene and target gene were assessed by real-time quantitative PCR (RT-qPCR), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and western blots. The biological function of critical molecules was investigated using in vitro and in vivo strategies including Cell Counting Kit-8 (CCK8), colony formation assay, flow cytometry, Fe2+/Fe3+, GSH/GSSG and the xenograft mice models. The ribosomal activities were determined by polysome profiling and O-propargyl-puromycin (OP-Puro) assay. The proteomics was conducted to clarify the downstream targets and the underlying mechanisms were validated by IHC, Pearson correlation analysis, protein stability and rescue assays. The clinical significance of the snoRNA was explored using the Cox proportional hazard model, receiver operating characteristic (ROC) and survival analysis.ResultsHere, we investigated the SNORA56, which was elevated in CRC tissues and plasma, and correlated with CRC prognosis. SNORA56 deficiency in CRC impaired proliferation and triggered ferroptosis, resulting in reduced tumorigenesis. Mechanistically, SNORA56 mediated the pseudouridylation of 28 S rRNA at the U1664 site and promoted the translation of the catalytic subunit of glutamate cysteine ligase (GCLC), an indispensable rate-limiting enzyme in the biosynthesis of glutathione, which can inhibit ferroptosis by suppressing lipid peroxidation.ConclusionsTherefore, the SNORA56/28S rRNA/GCLC axis stimulates CRC progression by inhibiting the accumulation of cellular peroxides, and it may provide biomarker and therapeutic applications in CRC.

Dataset Information

SPINK4 promotes colorectal cancer cell proliferation and inhibits ferroptosis.

Background

Methods

Results

Conclusions

Publications

SPINK4 promotes colorectal cancer cell proliferation and inhibits ferroptosis.

Similar Datasets

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