Role of Autophagy in Renal Cancer

Cao, Qi; Bai, Peng

doi:10.7150/jca.29285

Cited by 42 publications

(35 citation statements)

References 97 publications

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“…The current therapeutic therapies for RCC are mainly surgical resection, chemotherapy, and radiotherapy. However, the response to the mentioned treatments is un‐effective . Thus, we hope that the great progress in targeted treatments would emerge with the fully understanding of RCC pathogenesis in the future.…”

Section: Introductionmentioning

confidence: 99%

Establishment of cohesion 1 homolog 2 facilitates cell aggressive behaviors and induces poor prognosis in renal cell carcinoma

Wang

Liu

2020

Clinical Laboratory Analysis

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Background and aims Establishment of cohesion 1 homolog 2 (ESCO2) has been identified as an essential factor for cohesion in cell cycle in human multiple cancers. Nonetheless, its functional implication on prognosis and cellular behaviors of renal cell carcinoma (RCC) is rarely elucidated. We performed this study to detect the effects of ESCO2 in RCC progression. Methods We accessed The Cancer Genome Atlas (TCGA) database to evaluate the ESCO2 expression levels in tumor tissues, including 32 normal tissues and 289 tumor tissues. Quantitative real‐time PCR and Western blot were implemented for expression detection. After ESCO2 knockdown using siRNAs interference, functional experiments were conducted to explore the role of ESCO2, such as cell proliferation analysis and colony formation assay. Transwell assays for migration and invasion was also performed. Results In this study, ESCO2 was significantly increased in RCC tissues and cell lines. The RCC patients with high expression of ESCO2 were susceptible to unfavorable prognosis, and its expression has a marked association with clinical features containing age, gender, pathologic stage, and so on. Furthermore, knockdown of ESCO2 inhibited cell growth, invasion, and migration. Mechanistically, phosphorylation protein kinase B (AKT) and mammalian target of rapamycin (mTOR), proliferating cell nuclear antigen (PCNA), and p53 were all down‐regulated due to the ESCO2 inhibition. Conclusions Therefore, our results raised the possibility that ESCO2 may act as a promising option for tumor therapeutic interference by exhibiting enhanced selectivity over conventional chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Establishment of cohesion 1 homolog 2 facilitates cell aggressive behaviors and induces poor prognosis in renal cell carcinoma

Wang

Liu

2020

Clinical Laboratory Analysis

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“…In the recent years, another biological process, macroautophagy, referred to hereafter as autophagy, has attracted attention in the field of RCC 16 . Autophagy is a catabolic process by which cytoplasmic components are degraded by the lysosome, and is involved in both physiological and pathological conditions 17 .…”

Section: Introductionmentioning

confidence: 99%

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

et al. 2020

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Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12containing complex, distinct from the ATG5-ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

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“…The lower the level of autophagy is, the higher the stage and grade of ccRCC (13). Many drugs have been developed to promote autophagy in renal carcinoma and have achieved good therapeutic effects (14). However, these studies mainly focused on the influence of autophagy on the progression and treatment of ccRCC, and few researchers have studied the role of autophagy in the prognosis of ccRCC.…”

Section: Introductionmentioning

confidence: 99%

Identification of an Autophagy-Related Prognostic Signature for Clear Cell Renal Cell Carcinoma

et al. 2020

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Abnormal autophagy is closely related to the development of cancer. Many studies have demonstrated that autophagy plays an important role in biological function in clear cell renal cell carcinoma (ccRCC). This study aimed to construct a prognostic signature for ccRCC based on autophagy-related genes (ARGs) to predict the prognosis of ccRCC. Differentially expressed ARGs were obtained from ccRCC RNA-seq data in The Cancer Genome Atlas (TCGA) database. ARGs were enriched by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The prognostic ARGs used to construct the risk score models for overall survival (OS) and disease-free survival (DFS) were identified by Cox regression analyses. According to the median value of the risk score, patients were divided into a high-risk group and a low-risk group. The OS and DFS were analyzed by the Kaplan-Meier method. The predictive accuracy was determined by a receiver operating characteristic (ROC) curve analysis. Additionally, we performed stratification analyses based on different clinical variables and evaluated the correlation between the risk score and the clinical variables. The differentially expressed ARGs were mainly enriched in the platinum drug resistance pathway. The prognostic signatures based on 11 ARGs for OS and 5 ARGs for DFS were constructed and showed that the survive time was significantly shorter in the high-risk group than in the low-risk group (P < 0.001). The ROC curve for OS exhibited good predictive accuracy, with an area under the curve value of 0.738. In the stratification analyses, the OS time of the high-risk group was shorter than that of the low-risk group stratified by different clinical variables. In conclusion, an autophagy-related signature for OS we constructed can independently predict the prognosis of ccRCC patient, and provide a deep understanding of the potential biological mechanisms of autophagy in ccRCC.

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Role of Autophagy in Renal Cancer

Cited by 42 publications

References 97 publications

Establishment of cohesion 1 homolog 2 facilitates cell aggressive behaviors and induces poor prognosis in renal cell carcinoma

Establishment of cohesion 1 homolog 2 facilitates cell aggressive behaviors and induces poor prognosis in renal cell carcinoma

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

Identification of an Autophagy-Related Prognostic Signature for Clear Cell Renal Cell Carcinoma

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