p62 functions as an oncogene in colorectal cancer through inhibiting apoptosis and promoting cell proliferation by interacting with the vitamin D receptor

Zhang, Jing; Yang, Suzhen; Xu, Bing; Wang, Ting; Ying, Zheng; Liu, Fei; Ren, Fenggang; Jiang, Jiong; Shi, Haitao; Zou, Baicang; Lu, Xiaolan; Lu, Shemin; Liu, Dong

doi:10.1111/cpr.12585

Cited by 31 publications

(32 citation statements)

References 39 publications

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“…Valencia et al ( 44 ) also observed that the expression of p62 was declined in the stroma of several tumors, and as an anti-inflammatory tumor suppressor, p62 could inhibit tumor development by modulating the metabolism in the tumor stroma. In addition, low p62 expression is closely associated with poorer outcomes in patients with colorectal cancer, as patients with low p62 expression display the most aggressive tumor features ( 45 ). Thus, p62 is considered as a candidate for autophagy-modulating therapies to treat tumors ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA JPX promotes gastric cancer progression by regulating CXCR6 and autophagy via inhibiting miR‑197

Han

Liu

2020

Mol Med Rep

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Long non-coding RNAs (lncRNAs) serve a crucial role in gastric cancer (GC) progression. However, the molecular mechanism underlying lncRNA JPX transcript, XIST activator (JPX) in the tumorigenesis of GC is not completely understood. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to detect gene expression. A luciferase reporter gene assay was conducted to determine the relationship between microRNA (miR)-197 and JPX or C-X-C motif chemokine receptor 6 (CXCR6). Cell viability, migration and invasion were determined by performing MTT, wound healing and Transwell assays, respectively. The Cancer Genome Atlas database and the RT-qPCR results indicated that JPX expression was upregulated and miR-197 expression was downregulated in patients with GC and in GC cells. Moreover, high JPX expression and low miR-197 expression in patients with GC indicated poor prognosis. miR-197 expression was directly inhibited by JPX. Compared with the short hairpin RNA (sh) negative control (NC) group, NCI-N87 and MKN-45 cells in the shJPX group displayed decreased cell viability and invasion, as well as a wider scratch width. NCI-N87 and MKN-45 cells in the shJPX + miR-197 inhibitor group had increased viability and invasion, but a narrower scratch width compared with the shJPX group. It was also identified that miR-197 directly inhibited CXCR6 expression. miR-197 inhibited Beclin1 protein expression and promoted p62 protein expression. Compared with the NC group, NCI-N87 and MKN-45 cells in the miR-197 mimic group had decreased cell viability and invasion, and a wider scratch width. Enhanced cell viability and invasion, and a narrower scratch width was also observed in the miR-197 mimic + CXCR6 and miR-197 mimic + Beclin1 groups, compared with the miR-197 mimic group. Collectively, the results indicated that lncRNA JPX promoted GC progression by regulating CXCR6 and autophagy via inhibiting miR-197. Furthermore, JPX knockdown regulated GC cell phenotype by promoting miR-197.

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Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA JPX promotes gastric cancer progression by regulating CXCR6 and autophagy via inhibiting miR‑197

Han

Liu

2020

Mol Med Rep

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“…A large number of in vivo and in vitro studies have reported that SQSTM1 can promote tumor development and malignant phenotypes such as tumor growth, invasion, migration and apoptosis inhibition via multiple signal transduction pathways (13,25,26). Previous studies have con rmed the double-edged sword effect of autophagy in regulating tumors which highlighted the importance of SQSTM1 expression pattern.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of SQSTM1 in Breast Cancer: A Comprehensive Analysis

Liu

Sun

et al. 2020

Preprint

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Background: SQSTM1 (Sequestosome 1, p62) is degraded by activated autophagy and involved in the progression of in various types of cancers. However, the prognostic role and underlying regulation mechanism of SQSTM1 in the progression and development of breast cancer remain unclear.Methods: In this study, 1336 samples with available mRNA data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database and 27 formalin fixation and paraffin embedding (FFPE) tissue samples from the First Affiliated Hospital of Xi’an Jiaotong University were collected to evaluate SQSTM1 expression in mRNA and protein levels. Kaplan–Meier and Cox regression were used for revealing prognostic value in three independent breast cancer independent datasets. Tumor Immune Estimation Resource (TIMER) database and Gene Set Variation Analysis (GSVA) was used to explore the relationship of SQSTM1 mRNA expression and immune infiltration level in breast cancer. Dysregulation mechanisms of SQSTM1 were also explored including copy number variation (CNV), somatic mutation, epigenetic alterations and other transcription and post-transcription level using multiple datasets. Finally, Gene Set Enrichment Analysis (GSEA) was constructed to elucidate functional regulating performance of SQSTM1 in breast cancer.Results: The results showed that mRNA and protein level of SQSTM1 were significantly elevated in breast cancer and receiver operating characteristic (ROC) curve showed that p62 may act as diagnostic biomarker. Lower expression of SQSTM1 predicted better outcome through multiple datasets. It was also found that SQSTM1 correlated with immune infiltrates in breast cancer. Moreover, CNV and methylation of SQSTM1 DNA was correlated with SQSTM1 dysregulation and act as prognostic factors for breast cancer patients. Yet, somatic mutation status of SQSTM1 didn’t show any prognostic relevance. We also identified diverse transcription factors that directly bound to SQSTM1 DNA and the miRNAs which may regulate SQSTM1 mRNA. Finally, functional enrichment analysis revealed that SQSTM1 is related to cell signal transduction, oxidative stress and autophagy in breast cancer.Conclusion: Our findings revealed that overexpression of SQSTM1 significantly to poor survival and immune infiltrations in breast cancer. In addition, SQSTM1 plays a key role in the progression of breast cancer and might be a promising biomarker for the diagnosis and personalized treatment of breast cancer patients.

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“…Contrary, overexpression of p62 enhances the resistance to this chemotherapeutic agent, preventing cell death in response to this treatment ( 77 ). In the colorectal cancer cell line SW480, p62 proteins levels are found elevated ( 78 ), which correlates with active autophagy pathway compared to other cellular models of this type of cancer ( 79 ). Interestingly, silencing of p62 in SW480 cell line decreases cell proliferation and their capacity to invade and migrate.…”

Section: Molecular Features Of Autophagy Cytosolic Receptorsmentioning

confidence: 95%

“…Interestingly, silencing of p62 in SW480 cell line decreases cell proliferation and their capacity to invade and migrate. Additionally, injection of p62 depleted SW480 cells in mice decreases tumor growth and metastasis into the lung, compared to control cells ( 78 ). Similar findings have been reported with F5M2 and F4 cell lines of osteosarcoma, which present high levels of p62 ( 73 ).…”

Section: Molecular Features Of Autophagy Cytosolic Receptorsmentioning

confidence: 99%

Pro-Tumoral Functions of Autophagy Receptors in the Modulation of Cancer Progression

2021

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Cancer progression involves a variety of pro-tumorigenic biological processes including cell proliferation, migration, invasion, and survival. A cellular pathway implicated in these pro-tumorigenic processes is autophagy, a catabolic route used for recycling of cytoplasmic components to generate macromolecular building blocks and energy, under stress conditions, to remove damaged cellular constituents to adapt to changing nutrient conditions and to maintain cellular homeostasis. During autophagy, cells form a double-membrane sequestering a compartment termed the phagophore, which matures into an autophagosome. Following fusion with the lysosome, the cargo is degraded inside the autolysosomes and the resulting macromolecules released back into the cytosol for reuse. Cancer cells use this recycling system during cancer progression, however the key autophagy players involved in this disease is unclear. Accumulative evidences show that autophagy receptors, crucial players for selective autophagy, are overexpressed during cancer progression, yet the mechanisms whereby pro-tumorigenic biological processes are modulated by these receptors remains unknown. In this review, we summarized the most important findings related with the pro-tumorigenic role of autophagy receptors p62/SQSTM1, NBR1, NDP52, and OPTN in cancer progression. In addition, we showed the most relevant cargos degraded by these receptors that have been shown to function as critical regulators of pro-tumorigenic processes. Finally, we discussed the role of autophagy receptors in the context of the cellular pathways implicated in this disease, such as growth factors signaling, oxidative stress response and apoptosis. In summary, we highlight that autophagy receptors should be considered important players of cancer progression, which could offer a niche for the development of novel diagnosis and cancer treatment strategies.

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p62 functions as an oncogene in colorectal cancer through inhibiting apoptosis and promoting cell proliferation by interacting with the vitamin D receptor

Cited by 31 publications

References 39 publications

Long non‑coding RNA JPX promotes gastric cancer progression by regulating CXCR6 and autophagy via inhibiting miR‑197

Long non‑coding RNA JPX promotes gastric cancer progression by regulating CXCR6 and autophagy via inhibiting miR‑197

Prognostic Significance of SQSTM1 in Breast Cancer: A Comprehensive Analysis

Pro-Tumoral Functions of Autophagy Receptors in the Modulation of Cancer Progression

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