Polymorphisms in autophagy genes are genetic susceptibility factors in glioblastoma development

Bueno-Martínez, Elena; Lara-Almúnia, Mónica; Rodríguez-Arias, Carlos; Otero-Rodríguez, A.; Garfias-Arjona, S; González‐Sarmiento, Rogelio

doi:10.1186/s12885-022-09214-y

Cited by 11 publications

(4 citation statements)

References 60 publications

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“…Other ATGs including ATG5, ATG7 and FIP200 were linked to human cancers [ 164 , 165 , 166 ]. Furthermore, recent evidence revealed that six polymorphisms ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183, NOD2 rs2066844 and rs2066845 and ATG5 rs2245214 were associated with a predisposition to tumor development, particularly in glioblastoma [ 167 ]. In mouse models of KRAS-driven glioblastoma, stable knockdowns of ATG7, ATG13 and ULK1 demonstrated that autophagy is crucial for the initiation and sustained growth of glioma [ 168 ].…”

Section: Autophagy and Its Dual Role In The Regulation Of Cancermentioning

confidence: 99%

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

et al. 2022

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Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.

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Section: Autophagy and Its Dual Role In The Regulation Of Cancermentioning

confidence: 99%

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

et al. 2022

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“… 52 Bueno‐Martínez et al, could not find any association between ATG16L1 rs2241880 and the susceptibility to glioblastoma cancer. 53 An association of ATG16L1 rs2241880 polymorphism with HCC also has been observed in the Reuken et al study. They found a higher prevalence of G allele of ATG16L1 rs2241880 in patients with HCC compared to controls without HCC.…”

Section: Discussionmentioning

confidence: 57%

“…In 2021, Jamali et al evaluated the association of ATG16L1 rs2241880 polymorphism with colorectal cancer risk in an Iranian population and revealed that ATG16L1 rs2241880 increases the risk of colorectal cancer 52 . Bueno‐Martínez et al, could not find any association between ATG16L1 rs2241880 and the susceptibility to glioblastoma cancer 53 . An association of ATG16L1 rs2241880 polymorphism with HCC also has been observed in the Reuken et al study.…”

Section: Discussionmentioning

confidence: 97%

Autophagy‐related genes polymorphism in hepatitis B virus‐associated hepatocellular carcinoma: A systematic review

Yousefi,

Tabibzadeh,

Jawaziri

et al. 2024

Immunity Inflam & Disease

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BackgroundChronic hepatitis B (CHB) virus is the most common risk factor for developing liver malignancy. Autophagy is an essential element in human cell maintenance. Several studies have demonstrated that autophagy plays a vital role in liver cancer at different stages. In this systematic review, we intend to investigate the role of polymorphism and mutations of autophagy‐related genes (ATGs) in the pathogenesis and carcinogenesis of the hepatitis B virus (HBV).Materials and MethodsThe search was conducted in online databases (Web of Science, PubMed, and Scopus) using Viruses, Infections, Polymorphism, Autophagy, and ATG. The study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses criteria.ResultsThe primary search results led to 422 studies. By screening and eligibility evaluation, only four studies were relevant. The most important polymorphisms in hepatocellular carcinoma were rs2241880 in ATG16L1, rs77859116, rs510432, and rs548234 in ATG5. Furthermore, some polymorphisms are associated with an increased risk of HBV infection including, rs2241880 in ATG16L1 and rs6568431 in ATG5.ConclusionThe current study highlights the importance of rs2241880 in ATG16L1 and rs77859116, rs510432, and rs548234 in ATG5 for HBV‐induced HCC. Additionally, some mutations in ATG16L1 and ATG5 were important in risk of HBV infection. The study highlights the gap of knowledge in the field of ATG polymorphisms in HBV infection and HBV‐induced HCC.

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“…A whole exome sequencing for Jed66_GB indicated the presence of TC-rare damaging COSMIC variants detected in genes that were previously associated with glioblastoma including BCR activator of RhoGEF and GTPase ( BCR ) [ 43 , 44 ], TNF receptor associated protein 1 ( TRAP1 ) [ 45 – 47 ], DNA polymerase delta 1, catalytic subunit ( POLD1 ) [ 48 ], otopetrin 1 ( OTOP1 ) [ 49 ], tyrosine kinase 2 ( TYK2 ) [ 50 ], AT-rich interaction domain 1B ( ARID1B ) [ 51 ], CD48 molecule ( CD48 ) [ 52 ], ubiquitin specific peptidase 18 ( USP18 ) [ 53 ], nuclear receptor corepressor 1 ( NCOR1 ) [ 54 ], NFE2 Like BZIP Transcription Factor 2 ( NFE2L2 ) [ 55 ], and Kinesin Family Member 1A ( KIF1A ) [ 56 ]. For Jed41_GB, exome sequencing showed the presence of TC-rare damaging COSMIC variants detected in glioblastoma-associated genes including TP53 [ 43 , 44 , 57 ], LDL receptor related protein 1B ( LRP1B ) [ 44 , 58 ], adhesion G protein-coupled receptor E5 ( ADGRE5 ) [ 59 ], atrophin 1 ( ATN1 ) [ 60 ], autophagy related 2B ( ATG2B ) [ 61 , 62 ], MYC associated zinc finger protein ( MAZ ) [ 23 , 63 ], WNK lysine deficient protein kinase 1 ( WNK1 ) [ 64 , 65 ], UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) [ 66 ], and UDP glucuronosyltransferase family 1 member A6 ( UGT1A6 ) [ 67 ]. Not surprisingly, differences in functional characteristics between the two cell lines were demonstrated, consistent with the high inter-patient heterogeneity seen for glioblastoma [ 6 – 9 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

et al. 2022

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Background Glioblastomas (GBs) are characterised as one of the most aggressive primary central nervous system tumours (CNSTs). Single-cell sequencing analysis identified the presence of a highly heterogeneous population of cancer stem cells (CSCs). The proteins anterior gradient homologue 2 (AGR2) and glucose-regulated protein 78 (GRP78) are known to play critical roles in regulating unfolded protein response (UPR) machinery. The UPR machinery influences cell survival, migration, invasion and drug resistance. Hence, we investigated the role of AGR2 in drug-resistant recurrent glioblastoma cells. Methods Immunofluorescence, biological assessments and whole exome sequencing analyses were completed under in situ and in vitro conditions. Cells were treated with CNSTs clinical/preclinical drugs taxol, cisplatin, irinotecan, MCK8866, etoposide, and temozolomide, then resistant cells were analysed for the expression of AGR2. AGR2 was repressed using single and double siRNA transfections and combined with either temozolomide or irinotecan. Results Genomic and biological characterisations of the AGR2-expressed Jed66_GB and Jed41_GB recurrent glioblastoma tissues and cell lines showed features consistent with glioblastoma. Immunofluorescence data indicated that AGR2 co-localised with the UPR marker GRP78 in both the tissue and their corresponding primary cell lines. AGR2 and GRP78 were highly expressed in glioblastoma CSCs. Following treatment with the aforementioned drugs, all drug-surviving cells showed high expression of AGR2. Prolonged siRNA repression of a particular region in AGR2 exon 2 reduced AGR2 protein expression and led to lower cell densities in both cell lines. Co-treatments using AGR2 exon 2B siRNA in conjunction with temozolomide or irinotecan had partially synergistic effects. The slight reduction of AGR2 expression increased nuclear Caspase-3 activation in both cell lines and caused multinucleation in the Jed66_GB cell line. Conclusions AGR2 is highly expressed in UPR-active CSCs and drug-resistant GB cells, and its repression leads to apoptosis, via multiple pathways.

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Polymorphisms in autophagy genes are genetic susceptibility factors in glioblastoma development

Cited by 11 publications

References 60 publications

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

Autophagy‐related genes polymorphism in hepatitis B virus‐associated hepatocellular carcinoma: A systematic review

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

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