Overexpression of p62 is associated with poor prognosis and aggressive phenotypes in osteosarcoma

Lu, Yao; Wang, Qian; Zhou, Yong; Sun, Liang; Xue, Hao; Li, Ming; Zhang, Kun; Ren, Cheng; Duan, Ning; Liu, Hongliang; Zhang, Congming; Zhong, Li; Ma, Teng

doi:10.3892/ol.2018.8579

Cited by 10 publications

(12 citation statements)

References 32 publications

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“…These results revealed that, in the GCTB tumor microenvironment, p62 overexpression may be associated with tumorigenesis that is unrelated to bone metabolism. High p62 expression levels were associated with GCTB recurrence, a finding which agreed with previous findings in other bone tumors ( 6 , 7 ). Finally, p62 overexpression was identified as an independent indicator of poor prognosis of GCTB.…”

Section: Discussionsupporting

confidence: 91%

“…p62 (also known as sequestosome-1, SQSTM-1 or A170) is a crucial molecule in the regulation of cell growth, survival and proliferation (5). The p62 protein contains different types of protein-protein interaction domains, a characteristic that is consistent with its role as a versatile adaptor, especially for bone tumors and metabolic bone diseases (6) p62 is overexpressed in bone tumors, such as osteosarcoma (7) and myeloma (8). It is also associated with tumor invasion and metastasis (9).…”

Section: Introductionmentioning

confidence: 99%

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p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone

Liu

et al. 2020

Oncol Lett

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Giant cell tumor of bone (GCTB) is an intermediate (locally aggressive) bone tumor with a recurrence rate of >30% following surgery. GCTB recurrence is ultimately due to the proliferation of neoplastic stromal (NS) cells. However, the precise mechanism underlying the regulation of NS cell proliferation remains unknown. p62 protein is a multifunctional adaptor protein that exerts a positive role in bone tumors and metabolic bone diseases. In the present study, the mRNA and protein expression levels of p62 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in 8 paired fresh GCTB tumor tissues and adjacent normal cancellous bone tissues. The association between p62 expression level and patient prognosis was subsequently analyzed in 54 paraffin-embedded tumor specimens by immunohistochemistry assay. NS cells were isolated from GCTB primary cell culture, and the role of p62 was evaluated using in vitro cell proliferation, migration and invasion assays. The results revealed that p62 mRNA and protein were overexpressed in tumor tissues. High p62 expression levels were significantly associated with the recurrence of GCTB (P=0.001). The patients in the high p62 expression group had shorter 5-year recurrence-free survival rates compared with the patients in the low p62 expression group (P<0.001). Cox regression analysis identified p62 expression as an independent prognostic indicator of the recurrence-free survival of patients with GCTB (P<0.001). The in vitro experiments revealed that p62 downregulation inhibited NS cell proliferation, invasion and migration, and promoted apoptosis. In conclusion, it was found that p62 overexpression is associated with the recurrence of GCTB via the promotion of NS cell proliferation. Therefore, p62 could be a novel prognostic indicator, and a potential therapeutic target for GCTB.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone

Liu

et al. 2020

Oncol Lett

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“…Finally, via their downregulation, the virus may target the pleiotropic functions of p62/SQSTM1 and OPTN. For example, p62/SQSTM1 can inhibit the NF-B pathway, and for this reason, its overexpression in tumors promotes their survival (70). However, NF-B is important for HSV-1 replication (71).…”

Section: Discussionmentioning

confidence: 99%

The ICP0 Protein of Herpes Simplex Virus 1 (HSV-1) Downregulates Major Autophagy Adaptor Proteins Sequestosome 1 and Optineurin during the Early Stages of HSV-1 Infection

Waisner

Kalamvoki

2019

J Virol

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Herpes simplex virus 1 (HSV-1) infects mucosal epithelial cells and establishes lifelong infections in sensory neurons. Following reactivation, the virus is transferred anterograde to the initial site of infection or to sites innervated by infected neurons, causing vesicular lesions. Upon immunosuppression, frequent HSV-1 reactivation can cause severe diseases, such as blindness and encephalitis. Autophagy is a process whereby cell components are recycled, but it also serves as a defense mechanism against pathogens. HSV-1 is known to combat autophagy through the functions of the γ134.5 protein, which prevents formation of the autophagophore by binding to Beclin 1, a key factor involved in the elongation of the isolation membrane, and by redirecting the protein phosphatase 1α (PP1α) to dephosphorylate the translation initiation factor 2α (eIF2α) to prevent host translational shutoff. Other viral proteins that counteract innate immunity negatively impact autophagy. Here, we present a novel strategy of HSV-1 to evade the host through the downregulation of the autophagy adaptor protein sequestosome (p62/SQSTM1) and of the mitophagy adaptor optineurin (OPTN). This down-modulation occurs during the early steps of the infection. We also found that infected cell protein 0 (ICP0) of the virus mediates the down-modulation of the two autophagy adaptors in a mechanism independent of its E3 ubiquitin ligase activity. Cells depleted of either p62 or OPTN were able to mount greater antiviral responses, whereas cells expressing exogenous p62 displayed decreased virus yields. We conclude that downregulation of p62/SQSTM1 and OPTN is a viral strategy to counteract the host. IMPORTANCE Autophagy is a homeostatic mechanism of cells to recycle components, as well as a defense mechanism to get rid of pathogens. Strategies that HSV-1 has developed to counteract autophagy have been described and involve inhibition of autophagosome formation or indirect mechanisms. Here, we present a novel mechanism that involves downregulation of two major autophagy adaptor proteins, sequestosome 1 (p62/SQSTM1) and optineurin (OPTN). These findings generate the question of why the virus targets two major autophagy adaptors if it has mechanisms to block autophagosome formation. P62/SQSTM1 and OPTN proteins have pleiotropic functions, including regulation of innate immunity, inflammation, protein sorting, and chromatin remodeling. The decrease in virus yields in the presence of exogenous p62/SQSTM1 suggests that these adaptors have an antiviral function. Thus, HSV-1 may have developed multiple strategies to incapacitate autophagy to ensure replication. Alternatively, the virus may target another antiviral function of these proteins.

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“…Furthermore, patients with positive LC3B and negative HSP27 expression exhibited the highest 10-year survival rate (75%), whereas those with negative LC3B and positive HSP27 expression the worst (25%), indicating that LC3B and HSP27 were associated with favorable and poor outcomes in OS, respectively. Lu et al (80) demonstrated that p62 was detected in 54/70 OS samples (77.1%), and that its overexpression was associated with tumor size, metastasis, clinical stage and poor prognosis. Conversely, Ma et al (81) discovered that the 5-year survival rate of patients with OS with low p62 expression was lower than that of patients with high p62 expression, suggesting that decreased p62 expression was associated with higher metastasis and chemotherapy resistance rates in OS.…”

Section: Autophagy As a Prognostic Marker In Osmentioning

confidence: 99%

Targeting autophagy is a promising therapeutic strategy to overcome chemoresistance and reduce metastasis in osteosarcoma

Liao

et al. 2019

Int J Oncol

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Osteosarcoma (OS) is the most common primary bone malignancy, mainly affecting children and adolescents. Currently, surgical resection combined with adjuvant chemotherapy has been standardized for OS treatment. Despite great advances in chemotherapy for OS, its clinical prognosis remains far from satisfactory; this is due to chemoresistance, which has become a major obstacle to improving OS treatment. Autophagy, a catabolic process through which cells eliminate and recycle their own damaged proteins and organelles to provide energy, can be activated by chemotherapeutic drugs. Accumulating evidence has indicated that autophagy plays the dual role in the regulation of OS chemoresistance by either promoting drug resistance or increasing drug sensitivity. The aim of the present review was to demonstrate thatautophagy has both a cytoprotective and an autophagic cell death function in OS chemoresistance. In addition, methods to detect autophagy, autophagy inducers and inhibitors, as well as autophagy-mediated metastasis, immunotherapy and clinical prognosis are also discussed. Contents 1. Introduction 2. Methods of detecting autophagy 3. Autophagy inducers and inhibitors 4. Dual role of autophagy in OS chemoresistance 5. Autophagy and metastasis 6. Autophagy and immunotherapy 7. Autophagy as a prognostic marker in OS 8. Conclusion

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Overexpression of p62 is associated with poor prognosis and aggressive phenotypes in osteosarcoma

Cited by 10 publications

References 32 publications

p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone

p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone

The ICP0 Protein of Herpes Simplex Virus 1 (HSV-1) Downregulates Major Autophagy Adaptor Proteins Sequestosome 1 and Optineurin during the Early Stages of HSV-1 Infection

Targeting autophagy is a promising therapeutic strategy to overcome chemoresistance and reduce metastasis in osteosarcoma

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