Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence

Terabe, Takehito; Uchida, Fumihiko; Nagai, Hirokazu; Omori, Shoei; Ishibashi‐Kanno, Naomi; Hasegawa, Shogo; Yamagata, Kenji; Gosho, Masahiko; Yanagawa, Toru; Bukawa, Hiroki

doi:10.1016/j.humpath.2017.11.019

Cited by 28 publications

(23 citation statements)

References 35 publications

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“…Another study has reported that p62 accumulation was associated with the activation of a DNA damage response and elevated tumorigenesis . Recently, Terabe et al have also reported that the expression of autophagy‐related markers (LC3‐I/Ⅱ and p62) at the surgical margin might be an indicator of local recurrence and a poor prognosis in human OSCC.…”

Section: Discussionmentioning

confidence: 98%

“…19 Another study has reported that p62 accumulation was associated with the activation of a DNA damage response and elevated tumorigenesis. 20 Recently, Terabe et al 21 Inhibition of the mTOR activity has been reported to exert a potent antitumour effect in head and neck squamous cell carcinoma experimental systems, 22 and p-4E-BP1 has been shown to predict a poor prognosis in several types of cancer. [23][24][25][26] In our study, we found that the mTOR and 4E-BP1 levels and those of their corresponding phosphorylated proteins were significantly upregulated in the margin and tumour regions of OSCC and that mTOR/p-mTOR and 4E-BP1/ p-4E-BP1 showed a positive correlation.…”

Section: Discussionmentioning

confidence: 99%

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Simultaneous activation of impaired autophagy and the mammalian target of rapamycin pathway in oral squamous cell carcinoma

Yin

Feng

et al. 2019

J Oral Pathology Medicine

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Background The aim of this study was to conduct a comparative evaluation of the expression levels of autophagy markers and proteins of the mammalian target of rapamycin (mTOR) pathway in normal, margin and tumour tissues of patients with oral squamous cell carcinoma (OSCC). Materials and Methods Three regional specimens, including normal, margin and tumour tissues, were collected from 26 patients with OSCC. Western blotting, immunohistochemistry and immunofluorescence staining were performed to detect mTOR, eukaryotic translation initiation factor 4E‐binding protein 1 (4E‐BP1), p70 ribosomal S6 protein kinase (p70S6K) and the corresponding phosphorylated proteins, as well as the light chain 3 (LC3) and sequestosome‐1 (SQSTM1, also known as p62) autophagy indicators. Results LC3‐II, p62, mTOR, phospho‐mTOR, 4E‐BP1 and phospho‐4E‐BP1 were highly expressed in the margin and tumour groups. There were positive correlations between mTOR/phospho‐mTOR, mTOR/4E‐BP1, mTOR/phospho‐4E‐BP1, mTOR/p70S6K, LC3‐II/p62, LC3‐II/p70S6K, p62/4E‐BP1 and p62/phospho‐4E‐BP1 in normal group, while LC3‐II/p62, LC3‐II/mTOR, LC3‐II/4E‐BP1, LC3‐II/phospho‐4E‐BP1, phospho‐4E‐BP1/mTOR, phospho‐4E‐BP1/4E‐BP1 and p62/4E‐BP1 showed positive relationships in margin group; however, in tumour group, only mTOR/phospho‐mTOR, 4E‐BP1/phospho‐4E‐BP1 and phospho‐mTOR/p70S6K showed positive correlations. Conclusion The study suggests that autophagy is impaired in patients with OSCC and impaired autophagy and the mTOR pathway are simultaneously activated in OSCC cells.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Simultaneous activation of impaired autophagy and the mammalian target of rapamycin pathway in oral squamous cell carcinoma

Yin

Feng

et al. 2019

J Oral Pathology Medicine

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“…The expression of autophagy-related genes light chain 3 (LC3), Beclin-1 and p62 could be used as indicators of tumor recurrence and poor prognosis [46]. The transition from LC3 I to LC3 II is considered to be a sign of autophagy activity.…”

Section: Discussionmentioning

confidence: 99%

Silencing VEGF enhances the radiosensitivity of the radioresistant human nasopharyngeal carcinoma cell line CNE-2R by inhibiting autophagy through the activation of mTOR pathway

Chen

Lin

Chen

et al. 2020

Preprint

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Background: Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced to the radioresistance of tumors. The purpose of our study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma radioresistant cell line CNE-2R and the underlying mechanisms.Methods: The radiosensitivity of CNE-2R cells after silencing VEGF was detected by cell counting kit 8 (CCK-8) and clonogenic assay, cell cycle and apoptosis was subjected to flow cytometry. DNA damage and autophagy were observed by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation analysis. In vivo, the effect of VEGF on radiosensitivity of NPC cells was investigated through xenograft model, furthermore, immunohistochemistry and TUNEL assay were used to further verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion.Results: Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of CNE-2R cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in CNE-2R cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through the activation of mTOR pathway.Conclusion: VEGF depletion increased radiosensitivity of NPC radioresistant cell CNE-2R by suppressing autophagy via the activation of mTOR pathway.

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“…They clarified that the expression of LC3A and LC3B correlated with tumor recurrence and poor prognosis and the expression of p62 correlated with tumor recurrence. Therefore, they recommended that if these proteins are detected in normal mucosa near the surgical margin, strict follow‐up observation should be made or additional resection should be considered (Terabe et al, ). Otherwise, p62 can be considered as a target at the interface of aging, autophagy, and age‐related diseases (Bitto et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…We have elucidated the clinical implementation of p62 as a biomarker to predict malignant transformation of oral leukoplakia. Nevertheless, we investigated only p62 expression in oral leukoplakia, but there are other autophagy‐related markers, such as LC3A/B, associated with poor prognosis in oral squamous cell carcinoma (Terabe et al, ). Further investigations are expected to clarify the malignant transformation mechanisms, elucidate the interactions among biomarkers, and identify new biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Association between p62 expression and clinicopathological characteristics in oral leukoplakia

Yoshida

Terabe

Nagai

et al. 2019

Clinical & Exp Dental Res

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Objective Oral leukoplakia is keratinized lesions in the buccal mucosa, tongue, and gingiva. It is the most common oral precancerous lesion; oxidative stresses and irrelevant autophagy have been reported to be the cause of oncogenesis. p62, a cytoplasmic protein induced by oxidative stress, is an adaptor protein involved in the formation of protein aggregates and induction and inhibition of autophagy. The inhibition of autophagy induces p62 overexpression and promotes oncogenesis via the oncogenic signaling pathway. The aim of the present study was to elucidate the involvement of intracellular expression of p62 in oral leukoplakia and to address its potential clinical implementation as a biomarker to predict malignant transformation. Material and Methods Fifty samples from subjects with confirmed oral leukoplakia were evaluated by immunohistochemical staining for the expression of p62, 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), Ki67, and p53. Univariate and multivariate logistic regression analyses were performed to evaluate the association between p62, 8‐OHdG, Ki67, and p53 and clinical characteristics, including epithelial dysplasia. Results Significant associations were observed between p62 expression in the nucleus, p62 aggregation, and epithelial dysplasia (adjusted odds ratio [OR] = 5.75; 95% confidence interval [CI]: [1.28, 26.2]; .024 and OR = 6.16; 95% CI: [1.01, 37.4]; .048, respectively). The expression of p62 in the cytoplasm and the levels of 8‐OHdG, Ki67, and p53 were not significantly associated with epithelial dysplasia. A significant relationship was found between p62 expression in the nucleus and p53 expression (OR = 3.94; 95% CI: [1.14, 13.6]; .031). Conclusions The results suggested that p62 expression in the nucleus and p62 aggregation can be potential markers to predict the malignant transformation of oral leukoplakia.

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Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence

Cited by 28 publications

References 35 publications

Simultaneous activation of impaired autophagy and the mammalian target of rapamycin pathway in oral squamous cell carcinoma

Simultaneous activation of impaired autophagy and the mammalian target of rapamycin pathway in oral squamous cell carcinoma

Silencing VEGF enhances the radiosensitivity of the radioresistant human nasopharyngeal carcinoma cell line CNE-2R by inhibiting autophagy through the activation of mTOR pathway

Association between p62 expression and clinicopathological characteristics in oral leukoplakia

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