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2016 ; 18
(12
): 711-723
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Blocking Wnt Secretion Reduces Growth of Hepatocellular Carcinoma Cell Lines
Mostly Independent of ?-Catenin Signaling
#MMPMID27851986
Wang W
; Xu L
; Liu P
; Jairam K
; Yin Y
; Chen K
; Sprengers D
; Peppelenbosch MP
; Pan Q
; Smits R
Neoplasia
2016[Dec]; 18
(12
): 711-723
PMID27851986
show ga
Aberrant activation of Wnt/?-catenin signaling plays a key role in the onset and
development of hepatocellular carcinomas (HCC), with about half of them acquiring
mutations in either CTNNB1 or AXIN1. However, it remains unclear whether these
mutations impose sufficient ?-catenin signaling or require upstream Wnt ligand
activation for sustaining optimal growth, as previously suggested for colorectal
cancers. Using a panel of nine HCC cell lines, we show that siRNA-mediated
knockdown of ?-catenin impairs growth of all these lines. Blocking Wnt secretion,
by either treatment with the IWP12 porcupine inhibitor or knockdown of WLS,
reduces growth of most of the lines. Unexpectedly, interfering with Wnt secretion
does not clearly affect the level of ?-catenin signaling in the majority of
lines, suggesting that other mechanisms underlie the growth-suppressive effect.
However, IWP12 treatment did not induce autophagy or endoplasmic reticulum (ER)
stress, which may have resulted from the accumulation of Wnt ligands within the
ER. Similar results were observed for colorectal cancer cell lines used for
comparison in various assays. These results suggest that most colorectal and
liver cancers with mutations in components of the ?-catenin degradation complex
do not strongly rely on extracellular Wnt ligand exposure to support optimal
growth. In addition, our results also suggest that blocking Wnt secretion may aid
in tumor suppression through alternative routes currently unappreciated.