PLAGL2‐EGFR‐HIF‐1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity

Hu, Weiwei; Zheng, Shufang; Guo, Haixin; Dai, Beiying; Ni, Jiaping; Shi, Yawei; Bian, Hanrui; Li, Lanxin; Shen, Yi; Wu, Mo; Tian, Zhoutong; Liu, Guilai; Hossain, Amir; Yang, Hongbao; Wang, Duowei; Zhang, Qin; Yu, Jun; Birnbaumer, Lutz; Feng, Jifeng; Yu, Decai; Yang, Yong

doi:10.1002/hep.31293

Cited by 62 publications

(58 citation statements)

References 43 publications

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“…This is similar to our Kaplan-Meier survival analysis of the HCC gene dataset from TCGA. Moreover, increasing evidences speculate a positive regulatory role for HIF-2α in brosis, pathogenesis, metastasis, and resistance to anti-tumor treatments in HCC (22,(39)(40)(41)(42)(43)(44). Taken together, HIF-2α may be a potential target for the treatment of HCC.…”

Section: Discussionmentioning

confidence: 99%

Mild Chronic Hypoxia-Induced HIF-2α Interacts with c-MYC Through Competition with HIF-1α in Hepatocellular Carcinoma Proliferation

Han¹,

Yu²,

Li³

et al. 2020

Preprint

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Background: Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally, in which hypoxia and activated hypoxia-inducible factors (HIFs) play an important role. The sibling rivalry between HIF-1α and HIF-2α in hypoxic tumor growth and progression is still debated, including in HCC. This may be associated with the regulation of unique target genes, like c-MYC and mTOR. Methods: In the current study, twenty-six corresponding tumor- and non-tumor tissues, taken from patients with HCC, who underwent liver resection, were analyzed. In vitro, co-immunoprecipitation (Co-IP), Western blot, MTT assay, colony formation assay and Annexin V-FITC/PI staining apoptosis Assay were used to elucidate the relationship between HIF-1α and HIF-2α in hypoxic HCC cell proliferation and involved mechanism.Results: HIF-2α, but not HIF-1α, has a positive correlation with the expression of c-MYC in tumor tissues. In vitro, rapid HCC cell proliferation and increased interaction of HIF-2α/c-MYC were observed in mild chronic hypoxia. It was confirmed in situ proximity ligation assay and co-immunoprecipitation assay that although mild hypoxia up-regulated all HIF-1α, HIF-2α, and c-MYC, mTORC2-regulated HIF-2α competed with HIF-1α to bind c-MYC. HIF-2α knockdown, but not HIF-1α knockdown, decreased the expression of downstream c-MYC and mTORC1, suppressed hypoxic cell proliferation, and induced more cell apoptosis. Moreover, the inhibition of upstream protein PI3K by inhibitor Apitolisib counteracted this mechanism of adaptation to mild hypoxia hereby inducing cancer cells to apoptosis in HCC. Conclusions: In summary, this study highlights the role of HIF-2α but not HIF-1α in activating and binding c-MYC in HCC cell proliferation during mild chronic hypoxia response. PI3K/mTORC2/ HIF-2α/c-MYC axis plays a key role in this process. PI3K inhibitor Apitolisib is suggested as a potential treatment option for HCC, especially for rapidly growing HCC in mild chronic hypoxia.

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Section: Discussionmentioning

confidence: 99%

Mild Chronic Hypoxia-Induced HIF-2α Interacts with c-MYC Through Competition with HIF-1α in Hepatocellular Carcinoma Proliferation

Han¹,

Yu²,

Li³

et al. 2020

Preprint

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“…Hypoxia is an important feature of the microenvironment of solid tumors, and promotes malignancy. [32][33][34][35][36]44 In several previous studies microRNAs have reportedly mediated the cancer-promoting effects of hypoxia in various tumor types. 54 Zheng et al 41 suggested that hypoxia could drive tumorigenesis and metastasis in HCC by downregulating miR-196-5p.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia is a main feature of HCC, and strong evidence suggests that it may promote HCC progression by regulating characteristics associated with malignancy, including cancer stem-like properties, 32 proliferation, 33,34 metastasis, 35,36 and epithelial-mesenchymal transition 37,38 in both hypoxia-inducible factor 1-alpha (HIF1-α)-dependent and HIF1-α-independent manners. Dou et al 39 reported that hypoxia contributed to growth and metastasis by increasing the expression of tuftelin 1, which is an HCC oncoprotein.…”

Section: Introductionmentioning

confidence: 99%

<p>Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2</p>

Zhang

Huang²,

Tu³

et al. 2020

OTT

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Background: Sustained proliferation and active metastasis are hallmarks of cancer, and they pose major challenges to the development of treatments and a cure for hepatocellular carcinoma (HCC). Thus, the mechanisms of proliferation, migration, and invasion of cancer cells need to be investigated. Many studies indicate that dysregulation of microRNA plays important roles in the progression of HCC, but the role of placenta-specific microRNA (miR-512-3p) in HCC has not been systematically investigated. Purpose: In the current study, the expression, biological function, and mechanisms of miR-512-3p involvement in HCC were investigated. Methods: Real-time quantitative polymerase chain reaction assays were conducted to determine miR-512-3p levels in HCC tissues and cell lines. The StarBase V3.0 online platform was used to compare miR-512-3p levels in HCC tissues with TCGA data and to identify potential miR-512-3p target genes. Associations between miR-512-3p and clinicopathological characteristics were analyzed statistically. MTT, ethynyl deoxyuridine, and transwell assays were performed to assess cell viability, proliferation, migration, and invasion. The luciferase reporter gene assay was used to verify target genes. Recuse assays were performed to confirm whether large tumor suppressor kinase 2 (LATS2) participated in the regulatory effects of miR-512-3p on HCC cell proliferation and motility, and whether miR-512-3p mediated the tumor-promoting effects of hypoxia. Results: miR-512-3p was upregulated in HCC and it was associated with worse survival and unfavorable clinicopathological characteristics. Functional assays indicated that miR-512-3p contributed to HCC cell proliferation, migration, and invasion. Mechanistically, LATS2-a downstream target of miR-512-3p-mediated the tumor-promoting effects of miR-512-3p in HCC. Hypoxia could elevate miR-512-3p levels in HCC cells, and miR-512-3p partially mediated the tumor-promoting effects of hypoxia. Conclusion: Hypoxia-induced miR-512-3p contributes to HCC cell proliferation, migration, and invasion by targeting LATS2 and inhibiting the Hippo/yes-associated protein 1 pathways.

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“…PLAGL2 also enhances Wnt6 expression at the transcriptional level and promotes the progression of colorectal cancer 9 . In addition, the PLAGL2-EGFR-HIF-1/2α signalling loop induces the malignant phenotype of liver cancer and the chemotherapy resistance of erlotinib 10 . Although growing evidence has showed that PLAGL2 functions as a dominant oncogene in gastrointestinal cancers 7 , 11 , 12 , the exact role of PLAGL2 and the underlying mechanism in GC remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

PLAGL2 promotes the proliferation and migration of gastric cancer cells via USP37-mediated deubiquitination of Snail1

Zhao

Zhou

et al. 2021

Theranostics

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Rationale: PLAGL2 (pleomorphic adenoma gene like-2), a zinc finger PLAG transcription factor, is aberrantly expressed in several malignant tumors. However, the biological roles of PLAGL2 and its underlying mechanism in gastric cancer (GC) remain unclear. Methods: A series of experiments in vitro and in vivo were conducted to reveal the role of PLAGL2 in GC progression. Results: The data revealed that PLAGL2 promotes GC cell proliferation, migration, invasion, and EMT in vitro and in vivo . Mechanistically, we demonstrated the critical role of PLAGL2 in the stabilization of snail family transcriptional repressor 1 (Snail1) and promoting Snail1-mediated proliferation and migration of GC cells. PLAGL2 activated the transcription of deubiquitinase USP37, which then interacted with and deubiquitinated Snail1 protein directly. In addition, GSK-3β-dependent phosphorylation of Snail1 protein is essential for USP37-mediated Snail1 deubiquitination regulation. Conclusions: In general, PLAGL2 promotes the proliferation and migration of GC cells through USP37-mediated deubiquitination of Snail1 protein. This work provided potential therapeutic targets for GC treatment.

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PLAGL2‐EGFR‐HIF‐1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity

Cited by 62 publications

References 43 publications

Mild Chronic Hypoxia-Induced HIF-2α Interacts with c-MYC Through Competition with HIF-1α in Hepatocellular Carcinoma Proliferation

Mild Chronic Hypoxia-Induced HIF-2α Interacts with c-MYC Through Competition with HIF-1α in Hepatocellular Carcinoma Proliferation

<p>Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2</p>

PLAGL2 promotes the proliferation and migration of gastric cancer cells via USP37-mediated deubiquitination of Snail1

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