Fig. 8: Tumor suppressive effects of cholesterol inhibition in aPKC-deficient serrated tumors. | Nature Communications

Fig. 8: Tumor suppressive effects of cholesterol inhibition in aPKC-deficient serrated tumors.

From: Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

Fig. 8

a–d Prkcif/fPrkczf/f;Villin-Cre mice fed with regular chow or 1.25% cholesterol-supplemented diet for 3 months. Experimental design (a), serum total cholesterol levels (b Chow:n = 6 mice, Cholesterol:n = 5 mice), macroscopic images (c), total tumor number, and tumor load (d) Chow:n = 6 mice, Cholesterol:n = 6 mice). Red lines denote macroscopic tumors in (c). e–l Prkcif/fPrkczf/f;Villin-Cre mice treated with vehicle (n = 9) or 50 mg/kg of atorvastatin orally and 120 mg/kg of dipyridamole intraperitoneally (A/D) (n = 6) daily for 4 weeks. Experimental design (e), immunoblotting of small intestines (f), serum total cholesterol levels (g) macroscopic images (h), H&E staining of tumors (i), total tumor number and tumor load (j), cancer incidence (k), and numbers of sessile serrated lesions (SSL) and carcinomas (l). Red lines denote macroscopic tumors in h and microscopic tumor areas in (i). m, n Representative images of Ki67, ANXA10, and Cleaved Caspase 3 (CC3), staining (m) and their quantification (n) (Ki67, vehicle: n = 10 fields examined from 3 mice, A/D: n = 7 fields examined from 2 mice; ANXA10, vehicle: n = 7 fields examined from 2 mice, A/D: n = 7 fields examined from 2 mice; CC3, vehicle: n = 10 fields examined from 2 mice, A/D: n = 14 fields examined from 2 mice). Red arrows denote positive cells for CC3. o Representative images of immunofluorescence staining for SREBP2, ANXA10, and DAPI in vehicle and A/D treated tumors. p Graphical scheme of PKCλ/ι mediated cholesterol metabolic reprogramming in the serrated tumorigenesis. In the physiological state, PKCλ/ι directly phosphorylates SCAP promoting degradation through a ubiquitination cascade regulated by TRC8. Upon the loss of PKCλ/ι the subsequently increased SCAP stability results in the enhanced activation of SREBP2, the master regulator of cholesterol biosynthesis, to promote serrated CRC development. Data were presented as mean ± SEM. Two-tailed, unpaired Student’s t-test (b, d, g, j, l, n), two-tailed chi-square test (k). Scale bars, 5 mm (c, h), 1 mm (i), 50 μm (m, o). Source data are provided as a Source Data file.

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