Interleukin 1β-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP

Dang, Yunzhi; Chen, Jie; Feng, Weibo; Qiao, Chenyang; Han, Wei; Nie, Yongzhan; Wu, Kaichun; Fan, Daiming; Xia, Limin

doi:10.7150/thno.41712

Cited by 49 publications

(44 citation statements)

References 38 publications

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“…Previously, we analyzed the mRNA expression levels of 39 HOX genes in 10 normal liver tissues and 30 pairs of HCC tissues and adjacent nontumor tissues. Apart from HOXC10, we also found that the mRNA levels of HOXB5 were significantly upregulated in HCC tissues, and knockdown of HOXB5 inhibited the migration and invasion abilities of HCC cell line HCCLM3 24 . Another study reported that HOXB5 is upregulated in HCC tissues and overexpression of HOXB5 promoted HCC cell proliferation and inhibited cell apoptosis 25 .…”

Section: Introductionmentioning

confidence: 79%

Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation

He¹,

Huang²,

Liu³

et al. 2021

Theranostics

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Background: Since metastasis remains the main reason for HCC-associated death, a better understanding of molecular mechanism underlying HCC metastasis is urgently needed. Here, we elucidated the role of Homeobox B5 (HOXB5), a member of the HOX transcriptional factor family, in promoting HCC metastasis. Method: The expression of HOXB5 and its functional targets fibroblast growth factor receptor 4 (FGFR4) and C-X-C motif chemokine ligand 1 (CXCL1) were detected by immunohistochemistry. Luciferase reporter and chromatin immunoprecipitation assays were performed to measure the transcriptional regulation of target genes by HOXB5. The effects of FGFR4 and CXCL1 on HOXB5-mediated metastasis were analyzed by an orthotopic metastasis model. Results: Elevated expression of HOXB5 had a positive correlation with poor tumour differentiation, higher TNM stage, and indicated unfavorable prognosis. Overexpression of HOXB5 promoted HCC metastasis through transactivating FGFR4 and CXCL1 expression, whereas knockdown of FGFR4 and CXCL1 decreased HOXB5-enhanced HCC metastasis. Moreover, HOXB5 overexpression in HCC cells promoted myeloid derived suppressor cells (MDSCs) infiltration through CXCL1/CXCR2 axis. Either depletion of MDSCs by anti-Gr1 or blocking CXCL1-CXCR2 axis by CXCR2 inhibitor impaired HOXB5-mediated HCC metastasis. In addition, fibroblast growth factor 19 (FGF19) contributed to the HOXB5 upregulation through PI3K/AKT/HIF1α pathway. Overexpression of FGF15 (an analog of FGF19 in mouse) promoted HCC metastasis, whereas knockdown of HOXB5 significantly inhibited FGF15-enhanced HCC metastasis in immunocompetent mice. HOXB5 expression was positively associated with CXCL1 expression and intratumoral MDSCs accumulation in human HCC tissues. Patients who co-expressed HOXB5/CXCL1 or HOXB5/CD11b exhibited the worst prognosis. Furthermore, the combination of FGFR4 inhibitor BLU-554 and CXCR2 inhibitor SB265610 dramatically decreased HOXB5-mediated HCC metastasis. Conclusion: HOXB5 was a potential prognostic biomarker in HCC patients and targeting this loop may provide a promising treatment strategy for the inhibition of HOXB5-mediated HCC metastasis.

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Section: Introductionmentioning

confidence: 79%

Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation

He¹,

Huang²,

Liu³

et al. 2021

Theranostics

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“…Several studies have revealed the HOXC10 molecular mechanisms that regulate tumor development. Dysregulated HOXC10 affects tumorigenesis in different ways, including cell proliferation ( 10 , 43 – 45 ), the cell cycle ( 12 ), apoptosis ( 45 ), angiogenesis ( 32 ), invasion ( 46 – 49 ), drug resistance ( 52 , 53 , 55 ), and avoidance of immune destruction ( 41 ) ( Figure 3 ). In this section, we systematically summarize the functions and potential molecular mechanisms of HOXC10 in tumor occurrence, metastasis and drug resistance.…”

Section: Hoxc10 Is Involved In Tumorigenesis Metastasis and Drug Resistancementioning

confidence: 99%

“…Mechanistically, HOXC10 could activates the NF-κB pathway by binding to the p65 gene promotor and indirectly upregulating inflammatory cytokines (IL-6, TNF-α, TGF-β, EGF) in gastric cancer cells ( 58 ). Interestingly, inflammatory factor IL-1β can also promote HOXC10 expression via the JNK/c-Jun pathway and induce invasion and metastasis of hepatocellular carcinoma ( 46 ), indicating that HOXC10 can promote tumor metastasis by cooperating with inflammatory cytokines. Dang et al.…”

Section: Tumor Metastasis and Invasionmentioning

confidence: 99%

“…Moreover, HOXC10 expression have been reported to be positively correlated with poor pathologic stage, and poor prognosis ( 40 – 43 ). High HOXC10 expression is significantly to enhance tumor proliferation ( 10 , 43 – 45 ), invasiveness ( 46 – 49 ), recrudesce ( 50 , 51 ) and drug resistance ( 11 , 52 , 53 ). Reports suggest that anomalous HOXC10 expression is strongly associated with the occurrence and progression of cancers ( Table 1 ) and HOXC10 may be a potential prognostic factor and therapeutic target ( 42 , 51 , 56 ).…”

Section: Introductionmentioning

confidence: 99%

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Role of HOXC10 in Cancer

Fang

Wang

et al. 2021

Front. Oncol.

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The HOXC10 gene, a member of the HOX genes family, plays crucial roles in mammalian physiological processes, such as limb morphological development, limb regeneration, and lumbar motor neuron differentiation. HOXC10 is also associated with angiogenesis, fat metabolism, and sex regulation. Additional evidence suggests that HOXC10 dysregulation is closely associated with various tumors. HOXC10 is an important transcription factor that can activate several oncogenic pathways by regulating various target molecules such as ERK, AKT, p65, and epithelial mesenchymal transition-related genes. HOXC10 also induces drug resistance in cancers by promoting the DNA repair pathway. In this review, we summarize HOXC10 gene structure and expression as well as the role of HOXC10 in different human cancer processes. This review will provide insight into the status of HOXC10 research and help identify novel targets for cancer therapy.

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“…Hepatocellular carcinoma (HCC) ranked the fourth leading cause of mortality in patients suffering from malignant tumors in 2018 1 . Mortality from HCC is generally due to metastasis and postsurgical recurrence 2 - 3 . In these tumors, it is well known that there is dysregulation of gene transcription including gene mutations, the activation of oncogenes or the inactivation of tumor suppressor genes that work to promote tumor metastases.…”

Section: Introductionmentioning

confidence: 99%

Interactome analysis of gene expression profiles identifies CDC6 as a potential therapeutic target modified by miR-215-5p in hepatocellular carcinoma

Xu¹,

Huang²,

Hua³

et al. 2020

Int. J. Med. Sci.

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Background: Illustrating the pathogenesis of hepatocellular carcinoma (HCC) pathogenesis as well as identifying specific biomarkers are of great significance. Methods: The original CEL files were obtain from Gene Expression Omnibus, then affymetrix package was used to preprocess the CEL files, the function of DEGs were investigated by multiple bioinformatics approach. Finally, typical HCC cell lines and tissue samples were using to validate the role of CDC6 in vitro. Bioinformatics software was used to predict potential microRNA of CDC6. Luciferase assay was used to verify the interactions between CDC6 and microRNA. Results: A total of 445 DEGs were identified in HCC tissues based on two GEO datasets. GSEA results showed that the significant enriched gene sets were only associated with cell cycle signaling pathway. In the co-expression analysis, there were 370 hub genes from the blue modules were screened. We integrated DEGs, hub genes, TCGA cohort and GSEA analyses to further obtain 10 upregulated genes for validation. These genes were overexpressed in HCC tissues and negatively associated with overall and disease-free survival in HCC patients and related to immune cell infiltration in HCC microenvironments. Finally, Cell Division Cycle 6 (CDC6) was highlighted as one of the most probable genes among the 10 candidates participating in cancer process. The expression of CDC6 either in public datasets and HCC tissues sample were commonly high than the non-cancerous counterpart. Furthermore, we recognized that miR-215-5p, could directly bind to the 3'UTR of CDC6. In addition, CDC6 promoted proliferation via regulation of G1 phase checkpoint and was negative regulated by miR-215-5p to involve in the proliferation of HCC. Conclusion: Our study suggested that CDC6 served as a potential therapeutic target for HCC.

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Interleukin 1β-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP

Cited by 49 publications

References 38 publications

Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation

Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation

Role of HOXC10 in Cancer

Interactome analysis of gene expression profiles identifies CDC6 as a potential therapeutic target modified by miR-215-5p in hepatocellular carcinoma

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