
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 aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ 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 aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.
Inflammation, Mice, Knockout, STAT3 Transcription Factor, Skin Neoplasms, Carcinogenesis, Macrophages, NF-kappa B, 610, 500, Cell Polarity, Cell Cycle Proteins, Brief Communication, Receptors, Interleukin-4, Disease Models, Animal, Mice, Animals, Cell Adhesion Molecules, Protein Kinase C, Adaptor Proteins, Signal Transducing, Cell Proliferation, Signal Transduction, Skin
Inflammation, Mice, Knockout, STAT3 Transcription Factor, Skin Neoplasms, Carcinogenesis, Macrophages, NF-kappa B, 610, 500, Cell Polarity, Cell Cycle Proteins, Brief Communication, Receptors, Interleukin-4, Disease Models, Animal, Mice, Animals, Cell Adhesion Molecules, Protein Kinase C, Adaptor Proteins, Signal Transducing, Cell Proliferation, Signal Transduction, Skin
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| influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | Average | |
| impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network. | Top 10% |
