HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial-mesenchymal transition

Huan, Hongbo; Yang, Da‐Peng; Wen, Xudong; Chen, Xue-Jiao; Zhang, Liang; Wu, Lili; Bie, Ping; Xia, Feng

doi:10.1186/s13046-017-0559-4

Cited by 41 publications

(36 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, upregulation of USP37 promoted EMT, migration and invasion. Accumulation evidence has indicated that tumor cells undergoing EMT process are endowed with the trait of cancer stem-like cells [ 43 ], which further speculated USP37 as a CSC marker of breast cancer. In summary, our data showed that USP37 could regulate the migration, invasion, EMT of breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

Qin

Feng

et al. 2018

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundRecent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear.MethodsThe distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1.ResultsBioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway.ConclusionsThese findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0934-9) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

Qin

Feng

et al. 2018

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Functionally, proliferation and survival are preferentially affected in HOXA9-induced leukemia [150]. Besides, high expression of HOXB7 can promote cell proliferation and growth in colorectal [151] and hepatocellular carcinoma [152]. In colorectal cancer cells, HOXB7 is capable of inducing acceleration of G1-S transitions by activating PI3K/AKT and MAPK pathways, resulting in upregulation of p27Kip1 and cyclin D1 [151].…”

Section: Hox Genes In Cancer Progressionmentioning

confidence: 99%

The Role of HOX Transcription Factors in Cancer Predisposition and Progression

Huang

Wei

2019

Cancers

110

View full text Add to dashboard Cite

Homeobox (HOX) transcription factors, encoded by a subset of homeodomain superfamily genes, play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. Findings over the past decade have revealed that mutations in HOX genes can lead to increased cancer predisposition, and HOX genes might mediate the effect of many other cancer susceptibility factors by recognizing or executing altered genetic information. Remarkably, several lines of evidence highlight the interplays between HOX transcription factors and cancer risk loci discovered by genome-wide association studies, thereby gaining molecular and biological insight into cancer etiology. In addition, deregulated HOX gene expression impacts various aspects of cancer progression, including tumor angiogenesis, cell autophagy, proliferation, apoptosis, tumor cell migration, and metabolism. In this review, we will discuss the fundamental roles of HOX genes in cancer susceptibility and progression, highlighting multiple molecular mechanisms of HOX involved gene misregulation, as well as their potential implications in clinical practice.

show abstract

“…Aberrant signaling activation is involved in maintaining CSC traits in distinct cancers such as gastric and colorectal carcinoma, and HCC [18]. The activation of AKT signaling is implicated in HCC initiation and considered a hallmark to reflect the acquisition of CSC traits [19][20][21][22]. However, it is unclear how key upstream regulators of AKT signaling confer CSC traits to HCC cells.…”

Section: Introductionmentioning

confidence: 99%

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Lü

Tang

et al. 2020

J Hematol Oncol

View full text Add to dashboard Cite

Background: Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods: CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results: We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73-counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions: Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.

show abstract

HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial-mesenchymal transition

Cited by 41 publications

References 33 publications

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

The Role of HOX Transcription Factors in Cancer Predisposition and Progression

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Contact Info

Product

Resources

About