Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA)

Jasim, Saade Abdalkareem; salahdin, Omar dheyauldeen; Malathi, H.; Sharma, Neha; Rab, Safia Obaidur; Aminov, Zafar; Pramanik, Atreyi; Mohammed, Israa Hussein; Jawad, Mohammed Abed; Gabel, Benien C.

doi:10.1007/s12013-024-01423-5

Cell Biochem Biophys

2024

DOI: 10.1007/s12013-024-01423-5

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Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA)

Saade Abdalkareem Jasim,

Omar dheyauldeen salahdin,

H. Malathi

et al.

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2024

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The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

Shan,

Yin,

Zhan

et al. 2024

Sig Transduct Target Ther

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Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.

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The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

Shan,

Yin,

Zhan

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

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Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA)

Cited by 1 publication

References 233 publications

The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

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