Sequestsome-1/p62-targeted small molecules for pancreatic cancer therapy

Cuyler, Jacob; Murthy, Pranav; Spada, Neal; McGuire, Terence F.; Lotze, Michael T.; Xie, Xiang‐Qun

doi:10.1016/j.drudis.2021.09.011

Cited by 8 publications

(4 citation statements)

References 95 publications

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“…SQSTM1 , also known as P62, is a multidomain scaffold protein with well-established roles in autophagy and tumor necrosis factor alpha (TNFα)- and NF-κB-related signaling pathways ( Kirkin et al, 2009 ; Cha-Molstad et al, 2017 ; Cha-Molstad et al, 2018 ). However, researchers are increasingly finding that SQSTM1 has an essential and complex role in tumor progression ( Cuyler et al, 2022 ). Elevated SQSTM1 expression had been reported to support tumorigenesis ( Guo et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma

et al. 2022

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Background: Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and has a poor prognosis. In recent times, necroptosis has been reported to be involved in the progression of multiple cancers. However, the role of necroptosis in HCC prognosis remains elusive.Methods: The RNA-seq data and clinical information of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Differentially expressed genes (DEGs) and prognosis-related genes were explored, and the nonnegative matrix factorization (NMF) clustering algorithm was applied to divide HCC patients into different subtypes. Based on the prognosis-related DEGs, univariate Cox and LASSO Cox regression analyses were used to construct a necroptosis-related prognostic model. The relationship between the prognostic model and immune cell infiltration, tumor mutational burden (TMB), and drug response were explored.Results: In this study, 13 prognosis-related DEGs were confirmed from 18 DEGs and 24 prognostic-related genes. Based on the prognosis-related DEGs, patients in the TCGA cohort were clustered into three subtypes by the NMF algorithm, and patients in C3 had better survival. A necroptosis-related prognostic model was established according to LASSO analysis, and HCC patients in TCGA and ICGC were divided into high- and low-risk groups. Kaplan–Meier (K–M) survival analysis revealed that patients in the high-risk group had a shorter survival time compared to those in the low-risk group. Using univariate and multivariate Cox analyses, the prognostic model was identified as an independent prognostic factor and had better survival predictive ability in HCC patients compared with other clinical biomarkers. Furthermore, the results revealed that the high-risk patients had higher stromal, immune, and ESTIMATE scores; higher TP53 mutation rate; higher TMB; and lower tumor purities compared to those in the low-risk group. In addition, there were significant differences in predicting the drug response between the high- and low-risk groups. The protein and mRNA levels of these prognostic genes were upregulated in HCC tissues compared to normal liver tissues.Conclusion: We established a necroptosis-related prognostic signature that may provide guidance for individualized drug therapy in HCC patients; however, further experimentation is needed to validate our results.

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Section: Discussionmentioning

confidence: 99%

Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma

et al. 2022

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“…Notably, in a majority of gastrointestinal tumors such as hepatocellular carcinoma, colorectal carcinoma, intrahepatic cholangiocarcinoma, esophageal squamous cell carcinoma, and pancreatic carcinoma, p62 has been found to exert pro-oncogenic effects [ [2] , [3] , [4] , [5] , [6] , [7] ]. Elevated p62 expression can expedite the progression of various tumors, including hepatocellular carcinoma, colorectal carcinoma, and pancreatic carcinoma, through pathways such as p62-Keap 1-Nrf2, MEK/ERK signaling, NF-κB, among others [ [8] , [9] , [10] ]. Currently, existing research suggests elevated p62 expression in Gastric cancer (GC) tissues, potentially implicating its involvement in GC development.…”

Section: Introductionmentioning

confidence: 99%

SQSTM1/p62 promotes the progression of gastric cancer through epithelial-mesenchymal transition

Xu,

Zhu,

Zhu

et al. 2024

Heliyon

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“…p62 contains a ubiquitin-associated domain (UBA) at its C-terminus, through which it can recognize and bind ubiquitinated proteins [ 11 ]; Additionally, p62 contains an LC3-interacting region (LIR). LC3 is an autophagy-associated protein that binds to isolated and autophagosome membranes [ 12 ]. This allows for ubiquitinated proteins to be selectively directed by p62 to the isolation membrane where they form autolysosomes and are degraded together with p62.…”

Section: Introductionmentioning

confidence: 99%

p62 Is a Potential Biomarker for Risk of Malignant Transformation of Oral Potentially Malignant Disorders (OPMDs)

Takasaki,

Uchida,

Takaoka

et al. 2023

CIMB

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To determine the intracellular behavior of p62, a marker of selective autophagy, in oral potentially malignant disorders (OPMDs). This retrospective study includes 70 patients who underwent biopsy or surgical resection and were definitively diagnosed with OPMDs. Immunohistochemical staining for p62, XPO1, p53, and ki67 was performed on all samples and positive cell occupancy was calculated. We statistically investigated the correlation between protein expression in OPMDs and the association between malignant transformation, clinicopathological characteristics, and occupancy. ki67 expression was negatively correlated with p62 expression in the nucleus (p < 0.01) and positively correlated with p62 expression in the cytoplasm (p < 0.01). For malignant transformation, the expression of p62 in the nucleus (p = 0.03) was significantly lower in malignant transformation cases, whereas the expression of p62 in the cytoplasm (p = 0.03) and the aggregation expression (p < 0.01) were significantly higher. Our results suggest that the function of p62 is altered by its subcellular localization. In addition, defects in selective autophagy occur in cases of malignant transformation, suggesting that p62 is a potential biomarker of the risk of malignant transformation of OPMDs.

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Sequestsome-1/p62-targeted small molecules for pancreatic cancer therapy

Cited by 8 publications

References 95 publications

Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma

Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma

SQSTM1/p62 promotes the progression of gastric cancer through epithelial-mesenchymal transition

p62 Is a Potential Biomarker for Risk of Malignant Transformation of Oral Potentially Malignant Disorders (OPMDs)

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