Targeting the miR-34a/LRPPRC/MDR1 axis collapse the chemoresistance in P53 inactive colorectal cancer

Yang, Yang; Yuan, Hongyu; Zhao, Lianmei; Guo, Shichao; Hu, Sijun; Tian, Miaomiao; Nie, Yongzhan; Yu, Jiarui; Zhou, Chenguang; Niu, Junfeng; Wang, Guiying; Song, Yongmei

doi:10.1038/s41418-022-01007-x

Cited by 44 publications

(24 citation statements)

References 36 publications

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“…The signaling pathways involved in the regulation of p53 also include immune responses, non-coding RNAs and so on that exert tumor suppressive effects. 49 , 87 , 189 – 192 In the process of tumor development, p53 suppresses tumor transformation, 22 proliferation, 193 metastasis 194 and drug resistance 195 through multifaceted regulation. p53 has an exceptionally flexible biological response that is altered by changes in cell type, cell differentiation status, stress conditions, and different signals in the environment.…”

Section: Introductionmentioning

confidence: 99%

“…However, when TP53 is mutated, chemotherapy-induced inactivation of this pathway and the accumulation of LRPPRC and MDR1 promote drug resistance. 195 Mutated p53 binds to the miR-223 promoter and reduces its transcriptional activity, and the introduction of exogenous miR-223 makes tumor cells carrying mutated TP53 sensitive to treatment. 258 …”

Section: Introductionmentioning

confidence: 99%

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Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

231

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The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the “guardian of the genome”. Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an “undruggable” target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

231

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“…As one of the most common oncogenes, mutations in TP53 are associated with hepatocellular carcinoma differentiation, vascular invasion, serum alpha-fetoprotein (AFP) levels, and tumor stage ( 29 , 30 ). Meanwhile, accumulated LRPPRC and MDR1 promote tumor resistance when TP53 is mutated ( 31 ). Therefore, specific management of HCC patients with high expression of FAM72A is essential.…”

Section: Discussionmentioning

confidence: 99%

Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma

et al. 2022

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BackgroundThe family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown.MethodsData from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays.ResultsFirst, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4+ T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy.ConclusionsFAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.

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“…For example, in colorectal cancer (CRC), an investigation by [ 115 ] demonstrated that the RBP, leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) specifically bound to the mRNA of multidrug resistance 1 (MDR1), augmenting MDR1 mRNA stability and protein expression. Fortunately, LRPPRC is more recently found to be impaired by gossypol-acetic acid [ 115 ]. RBPs activities have been noticed in autophagosome processes in human cancer.…”

Section: Rbps Assume Diverse Types Of Functions In Mammalian Cellsmentioning

confidence: 99%

Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer

2022

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RNA-binding proteins (RBPs) have emerged as important players in multiple biological processes including transcription regulation, splicing, R-loop homeostasis, DNA rearrangement, miRNA function, biogenesis, and ribosome biogenesis. A large number of RBPs had already been identified by different approaches in various organisms and exhibited regulatory functions on RNAs’ fate. RBPs can either directly or indirectly interact with their target RNAs or mRNAs to assume a key biological function whose outcome may trigger disease or normal biological events. They also exert distinct functions related to their canonical and non-canonical forms. This review summarizes the current understanding of a wide range of RBPs’ functions and highlights their emerging roles in the regulation of diverse pathways, different physiological processes, and their molecular links with diseases. Various types of diseases, encompassing colorectal carcinoma, non-small cell lung carcinoma, amyotrophic lateral sclerosis, and Severe acute respiratory syndrome coronavirus 2, aberrantly express RBPs. We also highlight some recent advances in the field that could prompt the development of RBPs-based therapeutic interventions.

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Targeting the miR-34a/LRPPRC/MDR1 axis collapse the chemoresistance in P53 inactive colorectal cancer

Cited by 44 publications

References 36 publications

Targeting p53 pathways: mechanisms, structures and advances in therapy

Targeting p53 pathways: mechanisms, structures and advances in therapy

Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma

Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer

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