High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models

Luca Quagliata, Cristina Quintavalle, Manuela Lanzafame, Matthias S Matter, Chiara Novello, Luca di Tommaso, Tiziana Pressiani, Lorenza Rimassa, Luigi Tornillo, Massimo Roncalli, Clemente Cillo, Pierlorenzo Pallante, Salvatore Piscuoglio, Charlotte Ky Ng, Luigi M Terracciano

Research output: Contribution to journalArticle

Abstract

Hepatocellular carcinoma (HCC) represents the fifth and ninth cause of mortality among male and female cancer patients, respectively and typically arises on a background of a cirrhotic liver. HCC develops in a multi-step process, often encompassing chronic liver injury, steatosis and cirrhosis eventually leading to the malignant transformation of hepatocytes. Aberrant expression of the class I homeobox gene family (HOX), a group of genes crucial in embryogenesis, has been reported in a variety of malignancies including solid tumors. Among HOX genes, HOXA13 is most overexpressed in HCC and is known to be directly regulated by the long non-coding RNA HOTTIP. In this study, taking advantage of a tissue microarray containing 305 tissue specimens, we found that HOXA13 protein expression increased monotonically from normal liver to cirrhotic liver to HCC and that HOXA13-positive HCCs were preferentially poorly differentiated and had fewer E-cadherin-positive cells. In two independent cohorts, patients with HOXA13-positive HCC had worse overall survival than those with HOXA13-negative HCC. Using HOXA13 immunohistochemistry and HOTTIP RNA in situ hybridization on consecutive sections of 16 resected HCCs, we demonstrated that HOXA13 and HOTTIP were expressed in the same neoplastic hepatocyte populations. Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro. Our results provide compelling evidence of a role for HOXA13 in HCC development and highlight for the first time its ability to modulate response to sorafenib.

Original languageEnglish
Pages (from-to)95-105
Number of pages11
JournalLaboratory Investigation
Volume98
Issue number1
DOIs
Publication statusPublished - Jan 2018

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Hepatocellular Carcinoma
Hepatocytes
Liver
Long Noncoding RNA
MHC Class I Genes
Neoplasms
Homeobox Genes
Fatty Liver
Cadherins
Liver Neoplasms
In Vitro Techniques
sorafenib
Liver Cirrhosis
Genes
Agar
Embryonic Development
In Situ Hybridization
Immunohistochemistry
RNA
Cell Line

Keywords

  • Journal Article

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High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models. / Quagliata, Luca; Quintavalle, Cristina; Lanzafame, Manuela; Matter, Matthias S; Novello, Chiara; di Tommaso, Luca; Pressiani, Tiziana; Rimassa, Lorenza; Tornillo, Luigi; Roncalli, Massimo; Cillo, Clemente; Pallante, Pierlorenzo; Piscuoglio, Salvatore; Ng, Charlotte Ky; Terracciano, Luigi M.

In: Laboratory Investigation, Vol. 98, No. 1, 01.2018, p. 95-105.

Research output: Contribution to journalArticle

Quagliata, L, Quintavalle, C, Lanzafame, M, Matter, MS, Novello, C, di Tommaso, L, Pressiani, T, Rimassa, L, Tornillo, L, Roncalli, M, Cillo, C, Pallante, P, Piscuoglio, S, Ng, CK & Terracciano, LM 2018, 'High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models', Laboratory Investigation, vol. 98, no. 1, pp. 95-105. https://doi.org/10.1038/labinvest.2017.107
Quagliata, Luca ; Quintavalle, Cristina ; Lanzafame, Manuela ; Matter, Matthias S ; Novello, Chiara ; di Tommaso, Luca ; Pressiani, Tiziana ; Rimassa, Lorenza ; Tornillo, Luigi ; Roncalli, Massimo ; Cillo, Clemente ; Pallante, Pierlorenzo ; Piscuoglio, Salvatore ; Ng, Charlotte Ky ; Terracciano, Luigi M. / High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models. In: Laboratory Investigation. 2018 ; Vol. 98, No. 1. pp. 95-105.
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AU - Matter, Matthias S

AU - Novello, Chiara

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AU - Pressiani, Tiziana

AU - Rimassa, Lorenza

AU - Tornillo, Luigi

AU - Roncalli, Massimo

AU - Cillo, Clemente

AU - Pallante, Pierlorenzo

AU - Piscuoglio, Salvatore

AU - Ng, Charlotte Ky

AU - Terracciano, Luigi M

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N2 - Hepatocellular carcinoma (HCC) represents the fifth and ninth cause of mortality among male and female cancer patients, respectively and typically arises on a background of a cirrhotic liver. HCC develops in a multi-step process, often encompassing chronic liver injury, steatosis and cirrhosis eventually leading to the malignant transformation of hepatocytes. Aberrant expression of the class I homeobox gene family (HOX), a group of genes crucial in embryogenesis, has been reported in a variety of malignancies including solid tumors. Among HOX genes, HOXA13 is most overexpressed in HCC and is known to be directly regulated by the long non-coding RNA HOTTIP. In this study, taking advantage of a tissue microarray containing 305 tissue specimens, we found that HOXA13 protein expression increased monotonically from normal liver to cirrhotic liver to HCC and that HOXA13-positive HCCs were preferentially poorly differentiated and had fewer E-cadherin-positive cells. In two independent cohorts, patients with HOXA13-positive HCC had worse overall survival than those with HOXA13-negative HCC. Using HOXA13 immunohistochemistry and HOTTIP RNA in situ hybridization on consecutive sections of 16 resected HCCs, we demonstrated that HOXA13 and HOTTIP were expressed in the same neoplastic hepatocyte populations. Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro. Our results provide compelling evidence of a role for HOXA13 in HCC development and highlight for the first time its ability to modulate response to sorafenib.

AB - Hepatocellular carcinoma (HCC) represents the fifth and ninth cause of mortality among male and female cancer patients, respectively and typically arises on a background of a cirrhotic liver. HCC develops in a multi-step process, often encompassing chronic liver injury, steatosis and cirrhosis eventually leading to the malignant transformation of hepatocytes. Aberrant expression of the class I homeobox gene family (HOX), a group of genes crucial in embryogenesis, has been reported in a variety of malignancies including solid tumors. Among HOX genes, HOXA13 is most overexpressed in HCC and is known to be directly regulated by the long non-coding RNA HOTTIP. In this study, taking advantage of a tissue microarray containing 305 tissue specimens, we found that HOXA13 protein expression increased monotonically from normal liver to cirrhotic liver to HCC and that HOXA13-positive HCCs were preferentially poorly differentiated and had fewer E-cadherin-positive cells. In two independent cohorts, patients with HOXA13-positive HCC had worse overall survival than those with HOXA13-negative HCC. Using HOXA13 immunohistochemistry and HOTTIP RNA in situ hybridization on consecutive sections of 16 resected HCCs, we demonstrated that HOXA13 and HOTTIP were expressed in the same neoplastic hepatocyte populations. Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro. Our results provide compelling evidence of a role for HOXA13 in HCC development and highlight for the first time its ability to modulate response to sorafenib.

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