Heat‐Shock protein A12A is a novel PCNA‐binding protein and promotes hepatocellular carcinoma growth

Cheng, Hao; Cao, Xiaofei; Min, Xinxu; Zhang, Xiaojin; Kong, Qiuyue; Mao, Qian; Li, Rongrong; Xue, Bin; Fang, Lei; Liu, Li; Ding, Zhengnian

doi:10.1111/febs.15276

Cited by 11 publications

(10 citation statements)

References 41 publications

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“…The Akt activation in RCC cells was also not affected by HSPA12A ( Figure S19 ). When taken into account that our recent reports have shown a promoted proliferation of hepatocellular carcinoma cells by HSPA12A 53 , the current data suggest that the effects of CD147 and HSPA12A on proliferation are cancer cell type- and signaling activation-dependent.…”

Section: Discussionsupporting

confidence: 51%

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma

Min¹,

Zhang²,

Li³

et al. 2020

Theranostics

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Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.

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Section: Discussionsupporting

confidence: 51%

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma

Min¹,

Zhang²,

Li³

et al. 2020

Theranostics

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“…Subsequent studies revealed the downregulation of HSPA12A in the brains of patients with schizophrenia [17]. Recently, we have reported that HSPA12A is necessary for cerebral protection from stroke, for development of obesity and nonalcohol liver disease, and for growth of liver cancer [18][19][20][21]. Particularly, we found that HSPA12A facilitates angiogenesis in mouse liver carcinoma [21] and increases basal levels of ERK phosphorylation and VEGF expression in endothelial cells [21,22].…”

Section: Introductionmentioning

confidence: 70%

“…Recently, we have reported that HSPA12A is necessary for cerebral protection from stroke, for development of obesity and nonalcohol liver disease, and for growth of liver cancer [18][19][20][21]. Particularly, we found that HSPA12A facilitates angiogenesis in mouse liver carcinoma [21] and increases basal levels of ERK phosphorylation and VEGF expression in endothelial cells [21,22]. Therefore, it is possible that HSPA12A might promote angiogenesis to attenuate post-MI cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 80%

HSPA12A Stimulates p38/ERK-AP-1 Signaling to Promote Angiogenesis and Is Required for Functional Recovery Postmyocardial Infarction

et al. 2022

Oxidative Medicine and Cellular Longevity

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Angiogenesis plays a critical role in wound healing postmyocardial infarction (MI). However, there is still a lack of ideal angiogenic therapeutics for rescuing ischemic hearts clinically, suggesting that a more understanding regarding angiogenesis regulation is urgently needed. Heat shock protein A12A (HSPA12A) is an atypical member of the HSP70 family. Here, we demonstrated that HSPA12A was upregulated during endothelial tube formation, a characteristic of in vitro angiogenesis. Intriguingly, overexpression of HSPA12A promoted in vitro angiogenic characteristics including proliferation, migration, and tube formation of endothelial cells. By contrast, deficiency of HSPA12A impaired myocardial angiogenesis and worsened cardiac dysfunction post-MI in mice. The expression of genes related to angiogenesis (VEGF, VEGFR2, and Ang-1) was decreased by HSPA12A deficiency in MI hearts of mice, whereas their expression was increased by HSPA12A overexpression in endothelial cells. HSPA12A overexpression in endothelial cells increased phosphorylation levels and nuclear localization of AP-1, a transcription factor dominating angiogenic gene expression. Also, HSPA12A increased p38 and ERK phosphorylation levels, whereas inhibition of p38 or ERKs diminished the HSPA12A-promoted AP-1 phosphorylation and nuclear localization, as well as VEGF and VEGFR2 expression in endothelial cells. Notably, inhibition of either p38 or ERKs diminished the HSPA12A-promoted in vitro angiogenesis characteristics. The findings identified HSPA12A as a novel angiogenesis activator, and HSPA12A might represent a viable strategy for the management of myocardial healing in patients with ischemic heart diseases.

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“…Its synthesis and expression can reflect the proliferation of tumor cells. A significant increase in PCNA in HCC cells often accelerates cell proliferation, and the balance between cell proliferation and apoptosis is broken ( 38 ). Here, we show that both Huh7-derived exosomes and overexpressed miR-4800-3p obviously increased PCNA expression and finally promoted HCC cell proliferation and tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Exosomal miR-4800-3p Aggravates the Progression of Hepatocellular Carcinoma via Regulating the Hippo Signaling Pathway by Targeting STK25

et al. 2022

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BackgroundEmerging evidence has shown that exosome microRNAs (miRNAs) regulate the development of hepatocellular carcinoma (HCC). Here, the influences of miR-4800-3p on the progression of HCC were explored.Materials and MethodsThe expression of miR-4800-3p in the exosome derived by transforming growth factor beta 1 (TGF-β1)-treated HCC cells and the serum exosome isolated from HCC patients were identified by real-time PCR. The effects of TGF-β1 and the influences of Huh7-secreted exosomes and the effects of miR-4800-3p combined with/without STK25 on cell functions were explored using the EdU assay cloning experiments, wound healing assay, and Transwell assay. The corresponding molecular mechanisms were further detected using Western blot and real-time PCR assays. The combination of miR-4800-3p and STK25 was verified by the dual-luciferase and RNA pulldown assays. The influences of miR-4800-3p on the growth and epithelial–mesenchymal transformation (EMT) of implanted tumors were tested in vivo and further confirmed by Western blot.ResultsThe miR-4800-3p expression was highly expressed in both exosomes derived by TGF-β1-treated HCC cells and the serum exosomes of HCC patients. In the cases of treatment with both Huh7-derived exosomes, the level of miR-4800-3p expression was highest, and the treatment of TGF-β1 could greatly promote the proliferation, stemness, migration, and invasion of HCC cells via upregulating the markers of stemness and EMT, including CD44, CD133, OCT4, N-cadherin, E-cadherin, and ZO-1. Similar results could be obtained when miR-4800-3p was overexpressed in HCC cells. Furthermore, downregulation of STK25 expression, a direct target gene of miR-4800-3p, could greatly rescue the malignant biological behaviors aggravated by overexpression of miR-4800-3p. This was achieved by suppressing the expression of CD44, CD133, OCT4, N-cadherin, and PCNA and activating the Hippo pathway while increasing E-cadherin and ZO-1. Similar results were also obtained in vivo that knockdown of miR-4800-3p expression suppressed tumor growth induced by Huh7-derived exosomes by mediating the EMT markers and the Hippo signaling pathway.ConclusionExosomal miR-4800-3p could accelerate HCC development by regulating the Hippo signal by targeting STK25, which could be used as a new therapeutic target for HCC treatment.

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Heat‐Shock protein A12A is a novel PCNA‐binding protein and promotes hepatocellular carcinoma growth

Cited by 11 publications

References 41 publications

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma

HSPA12A Stimulates p38/ERK-AP-1 Signaling to Promote Angiogenesis and Is Required for Functional Recovery Postmyocardial Infarction

Exosomal miR-4800-3p Aggravates the Progression of Hepatocellular Carcinoma via Regulating the Hippo Signaling Pathway by Targeting STK25

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