| First Author | Vorhagen S | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 37 | Pages | 5136-5146 |
| PubMed ID | 29789715 | Mgi Jnum | J:274161 |
| Mgi Id | MGI:6296560 | Doi | 10.1038/s41388-018-0313-1 |
| Citation | Vorhagen S, et al. (2018) Shared and independent functions of aPKClambda and Par3 in skin tumorigenesis. Oncogene 37(37):5136-5146 |
| abstractText | The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKClambda serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKClambda genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKClambda, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKClambda function as a complex to promote tumorigenesis. Molecularly, Par3/aPKClambda cooperate to promote Akt, ERK and NF-kappaB signaling during tumor initiation to sustain growth, whereas aPKClambda dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKClambda cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKClambda and Par3 promote a tumor-permissive environment. Importantly, aPKClambda also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKClambda cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling. |
