Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Dec 22;13(1):10.
doi: 10.3390/cancers13010010.

Roles of the HOX Proteins in Cancer Invasion and Metastasis

Ana Paço  1 , Simone Aparecida de Bessa Garcia  2 , Joana Leitão Castro  2 , Ana Rita Costa-Pinto  2 , Renata Freitas  2   3
Affiliations
Review

Roles of the HOX Proteins in Cancer Invasion and Metastasis

Ana Paço et al. Cancers (Basel). .

Abstract

Invasion and metastasis correspond to the foremost cause of cancer-related death, and the molecular networks behind these two processes are extremely complex and dependent on the intra- and extracellular conditions along with the prime of the premetastatic niche. Currently, several studies suggest an association between the levels of HOX genes expression and cancer cell invasion and metastasis, which favour the formation of novel tumour masses. The deregulation of HOX genes by HMGA2/TET1 signalling and the regulatory effect of noncoding RNAs generated by the HOX loci can also promote invasion and metastasis, interfering with the expression of HOX genes or other genes relevant to these processes. In this review, we present five molecular mechanisms of HOX deregulation by which the HOX clusters products may affect invasion and metastatic processes in solid tumours.

Keywords: HMGA2/TET1/HOXA signalling pathway; HOX; TGFβ signalling; epithelial-to-mesenchymal transition; invasion and metastasis; lncRNAs; microRNAs.

PubMed Disclaimer

Conflict of interest statement

Authors declare there is no conflict of interests.

Figures

Figure 1
Figure 1
Metastatic process and involved HOX genes, regarding breast cancer. After cell transformation, a mass is rapidly formed in a specific organ of the body, designated as primary tumour. With the formation of new blood vessels surrounding the primary tumour (angiogenesis), growth is stimulated by the flux of nutrients and oxygen. Then, cells from the primary tumour may acquire motility going through the basement membrane into the blood vessels (intravasation). Once in circulation, metastatic tumour cells stop its progress adhering to the basement membrane of a new tissue site (extravasation). Finally, cancer cells start to proliferate in the new location, forming a new tumour mass. In breast cancer, overexpression of HOXB7, along with the upregulation of the indicated molecules, and downregulation of HOXD10 and HOXB3 have been linked to the metastatic process.
Figure 2
Figure 2
HMGA2/TET1/HOXA signalling in breast cancer cells. Depletion of the architectural transcription factor high mobility group AT-hook 2 (HMGA2) induces TET1 (ten–eleven translocation methylcytosine dioxygenases). This molecule initiates demethylation of DNA and is associated with tumorigenesis in many cancers. TET1 binds and demethylates its own promoter and the promoters of HOXA7 and HOXA9, increasing their expression, which may result in the inhibition of breast cancer growth and metastasis, already demonstrated for HOXA9 using mouse xenografts [35]. The demethylation promoted by TET1 allows the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and this to 5-formylcytosine (5fC), which in turn is converted in to 5-carboxycytosine (5caC) and at the end in an unmodified cytosine (C).
Figure 3
Figure 3
TGFβ signalling pathway in breast cancer cells. The reception of the TGFβ signals by the TGFβ receptor type II allows the phosphorylation of the TGFβ receptor type I. Subsequently this favour the phosphorylation of SMAD2/3 proteins that can in turn interact with the protein SMAD4. This complex of proteins controls the expression of TGFβ target genes, affecting cellular processes, such as proliferation, apoptosis, metastasis, and angiogenesis. The expression of the TGFβ’s genes is regulated by HOX transcriptional factors, as HOXB7 in breast cancer. After its transcription (nucleus) and translation (cytoplasm), TGFβ ligands are exported to the ECM, where they recognize and are recognized by TGFβ receptors type II.
Figure 4
Figure 4
Examples of HOX genes involved in the activation or inhibition of the epithelial to mesenchymal transition (EMT) in breast cancer. Epithelial cells present apical–basal polarity and are maintained together by tight junctions, adherens junctions and desmosomes. Hemidesmosomes maintain epithelial cells together with basement membrane. At the end of this process, epithelial cells present mesenchymal characteristics as the absence of apical–basal polarity and presence of motility capacity. HOXA5 is known to inhibit the EMT via upregulation of CDH1 in the adherens junctions, while HOXB7 induce the EMT downregulating the epithelial proteins: Claudin-1, Claudin-7, Claudin-4 and CDH1, and upregulating vimentin and α-SMA.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dillekås H., Rogers M.S., Straume O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019;8:5574–5576. doi: 10.1002/cam4.2474. - DOI - PMC - PubMed
    1. Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. - DOI - PubMed
    1. Massagué J., Obenauf A.C. Metastatic colonization by circulating tumour cells. Nature. 2016;529:298–306. doi: 10.1038/nature17038. - DOI - PMC - PubMed
    1. Damrauer J.S., Phelps S.N., Amuchastegui K., Lupo R., Mabe N.W., Walens A., Kroger B.R., Alvarez J.V. Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K-Akt Inhibition. Mol. Cancer Res. Mcr. 2018;16:599–609. doi: 10.1158/1541-7786.MCR-17-0492. - DOI - PMC - PubMed
    1. Tabassum D.P., Polyak K. Tumorigenesis: It takes a village. Nat. Rev. Cancer. 2015;15:473–483. doi: 10.1038/nrc3971. - DOI - PubMed

LinkOut - more resources