Loss Of Pkhd1 Promotes Intestinal Tumorigenesis In Apc Mice

PKHD1 (Polycystic Kidney and Hepatic Disease 1), the causal gene of ARPKD (Autosomal Recessive Polycystic Kidney Disease), has been proposed to play a role in the colorectal carcinogenesis. To validate this role, the mouse models with Pkhdl mutation(Pkhd1-/-) was used to mate with in the same genetic background. The resulting ApcMin/+ mice with and without Pkhd1-/- alleles were randomly sorted into two experimental groups (i.e. Pkhd1-/-;ApcMin/+ n=36; ApcMin/+ n=23). The tumorigenic susceptibility between Pkhd1-/-;ApcMin+ and ApcMin/+ mice was compared. The number, size and pathology of intestinal tumors in the mice were analyzed at the age of 1-,3-, and 6-month-old. There is no statistical difference in tumor number and size between 1-month-old ApcMin/+ and Pkhd1-/-;ApcMin/+ mice. However, the number and size of the intestinal tumors in 3- and 6-month-old Pkhd1-/-;ApcMin/+ mice are significantly increased than that of ApcMin/+ mice alone (P=0.017, P=0.022). In addition, the pathology of tumors was also analyzed between the two mouse groups. There is no pathological difference between 1-month-old ApcMin/+ and Pkhd1-/-;ApcMin/+ mice. However, at 3-month-old, Pkhd1-/-;ApcMin/+ mice exhibited severer atypical hyperplasia in the intestinal tumor than ApcMin/+ mice do; while at 6-month-old, focal necrosis can be often seen in intestinal tumors of Pkhd1-/-;ApcMin/+ mice, but not of ApcMin/+ mice. Strikingly, tumor infiltration into the muscular mucosa was also seen in a 6-month-old Pkhd1-/-;ApcMin/+ mice. Survival rate was also investigated between the two group mice. There was no statistically survival difference between ApcMin/+ and Pkhd1-/-;ApcMin/+ mice. In summary, that loss of Pkhdl promotes the intestinal tumorigenesis and induces tumor malignant transformation in ApcMin/+ mice.