First name
Simona
Last name
Monterisi
Year of Study
Research Center
Thesis Title
HOXB7 in lung cancer: a novel role in stem cell and iPS biology
Thesis Abstract
Current diagnostic tools do not allow prognostic evaluation of patients with early
stage lung cancer or selection of patients that might bene t from adjuvant chemotherapy.
Therefore, the identi cation of novel prognostic markers in early-stage lung cancer
is paramount. In this scenario, the transcription factor HOXB7, belonging to the homeobox
family, has been shown to correlate with poor prognosis in di erent types of cancer
and recently also in stage I lung adenocarcinoma.
To better understand the prognostic implication of alterations in HOXB7 expression
in lung cancer, we performed a bioinformatics analysis of multiple lung cancer
expression datasets in order to identify gene sets representing cancer-relevant biological
functions enriched in high-HOXB7 expressing tumors. We found several gene sets enriched
in high-HOXB7 expressing tumors representing molecular mechanisms involved
in epithelial to mesenchymal transition, in cancer progression, and, interestingly, in
stemness and cellular reprogramming. Based on these results, we hypothesized that
HOXB7 may have a role in the expansion of the stem cell compartment in cancer, a
mechanism that has been shown to be a hallmark of enhanced tumorigenicity and of
increased metastatic potential.
Analysis of the stem-related surface marker CD90 revealed that overexpression of
HOXB7 in lung cells increases the CD90high sub population. CD90high, but not CD90low
cells, are able to form spheroids, which is an hallmark of stemness. Indeed, the sphere
forming eciency of normal lung BEAS-2B cells was 22% and 1.64% in CD90high and
CD90low populations, respectively. In addition, we found that silencing of LIN28B counteracts the expansion of the CD90high population. LIN28B was recently described as
an oncogene that regulates the cancer stem cell compartment. We found that LIN28B
is under the direct transcriptional control of HOXB7. Therefore, we propose a novel
molecular mechanism driven by HOXB7 and can increase stem-like properties in lung
cells.
We further demonstrated that the HOXB7-LIN28B axis plays an important role in
reprogramming of adult cells into induced pluripotent stem cells (iPS). Indeed, HOXB7
may enhance the reprogramming eciency achieved by the three genes OCT4, KLF4,
SOX2 in both mouse embryonic broblast and human epithelial BEAS-2B cells by
substituting MYC in the transcription factor cocktail of reprogramming factors used by
Yamanaka. Of note, LIN28B silencing strongly decreases the number of reprogrammed
colonies in high-HOXB7 expressing cells.
These ndings suggest that HOXB7, through transcriptional induction of the LIN28B
gene, activates a program relevant for stem/iPS cell biology and for tumor progression,
possibly opening a new line of research for the development of more e ective therapies
for metastatic lung cancer patients.
stage lung cancer or selection of patients that might bene t from adjuvant chemotherapy.
Therefore, the identi cation of novel prognostic markers in early-stage lung cancer
is paramount. In this scenario, the transcription factor HOXB7, belonging to the homeobox
family, has been shown to correlate with poor prognosis in di erent types of cancer
and recently also in stage I lung adenocarcinoma.
To better understand the prognostic implication of alterations in HOXB7 expression
in lung cancer, we performed a bioinformatics analysis of multiple lung cancer
expression datasets in order to identify gene sets representing cancer-relevant biological
functions enriched in high-HOXB7 expressing tumors. We found several gene sets enriched
in high-HOXB7 expressing tumors representing molecular mechanisms involved
in epithelial to mesenchymal transition, in cancer progression, and, interestingly, in
stemness and cellular reprogramming. Based on these results, we hypothesized that
HOXB7 may have a role in the expansion of the stem cell compartment in cancer, a
mechanism that has been shown to be a hallmark of enhanced tumorigenicity and of
increased metastatic potential.
Analysis of the stem-related surface marker CD90 revealed that overexpression of
HOXB7 in lung cells increases the CD90high sub population. CD90high, but not CD90low
cells, are able to form spheroids, which is an hallmark of stemness. Indeed, the sphere
forming eciency of normal lung BEAS-2B cells was 22% and 1.64% in CD90high and
CD90low populations, respectively. In addition, we found that silencing of LIN28B counteracts the expansion of the CD90high population. LIN28B was recently described as
an oncogene that regulates the cancer stem cell compartment. We found that LIN28B
is under the direct transcriptional control of HOXB7. Therefore, we propose a novel
molecular mechanism driven by HOXB7 and can increase stem-like properties in lung
cells.
We further demonstrated that the HOXB7-LIN28B axis plays an important role in
reprogramming of adult cells into induced pluripotent stem cells (iPS). Indeed, HOXB7
may enhance the reprogramming eciency achieved by the three genes OCT4, KLF4,
SOX2 in both mouse embryonic broblast and human epithelial BEAS-2B cells by
substituting MYC in the transcription factor cocktail of reprogramming factors used by
Yamanaka. Of note, LIN28B silencing strongly decreases the number of reprogrammed
colonies in high-HOXB7 expressing cells.
These ndings suggest that HOXB7, through transcriptional induction of the LIN28B
gene, activates a program relevant for stem/iPS cell biology and for tumor progression,
possibly opening a new line of research for the development of more e ective therapies
for metastatic lung cancer patients.
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