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TPL2 is an oncogenic driver in keratocanthoma and squamous cell carcinoma

Lee, Jun Han; Lee, Joo Hyung; Lee, Sang Hyuk; Do, Sung Im; Cho, Sung Dae; Forslund, Ola LU ; Inn, Kyung Soo; Lee, Jeong Sang; Deng, Fang Ming and Melamed, Jonathan, et al. (2016) In Cancer Research 76(22). p.6712-6722
Abstract

Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 over-expression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-κB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2... (More)

Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 over-expression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-κB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is over-expressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development.

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publication status
published
subject
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Cancer Research
volume
76
issue
22
pages
11 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:84995539023
  • wos:000388742100028
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-15-3274
language
English
LU publication?
yes
id
72ed203d-0f81-4ddc-8236-359e037eaa27
date added to LUP
2016-12-05 08:30:10
date last changed
2017-09-18 11:29:50
@article{72ed203d-0f81-4ddc-8236-359e037eaa27,
  abstract     = {<p>Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 over-expression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-κB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is over-expressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development.</p>},
  author       = {Lee, Jun Han and Lee, Joo Hyung and Lee, Sang Hyuk and Do, Sung Im and Cho, Sung Dae and Forslund, Ola and Inn, Kyung Soo and Lee, Jeong Sang and Deng, Fang Ming and Melamed, Jonathan and Jung, Jae U. and Jeong, Joseph H.},
  issn         = {0008-5472},
  language     = {eng},
  month        = {11},
  number       = {22},
  pages        = {6712--6722},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {TPL2 is an oncogenic driver in keratocanthoma and squamous cell carcinoma},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-15-3274},
  volume       = {76},
  year         = {2016},
}