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MACC1 in esophageal and gastric adenocarcinomas (AGE/S): An aggressive but drugable oncogene
13 August 2018 (online)
AGE/S are characterized by early metastasis and poor survival. MACC1 (Metastasis associated in colon cancer 1) acts in colon cancer as a metastasis inducer and leads to reduced survival. In this project, we aimed to illuminate the role and potential of inhibition of MACC1 in AGE/S.
The AGE/S cell lines FLO1 (no endogenous MACC1 expression), selected for lentiviral MACC1 overexpression (FLO1/MACC1) and OE33 (high endogenous MACC1 expression), selected for stable lentiviral MACC1 knockdown (OE33/shMACC1) have been used. As controls a lentiviral empty vector for FLO1 (FLO1/CTRL) and a scrambled sh-control for OE33 (OE33/shCTRL) were used and functional analyzed for in vitro proliferation and migration. For in vivo analysis FLO1 cell clones were injected intrasplenically in NOG mice. Pharmacological MACC1 inhibition was tested in vitro and vivo using the MEK inhibitor AZD6244. To analyze the role of MACC1 in AGE/S patients, 360 untreated primary AGE/S tumors with a medium follow-up of 126 months were stained for MACC1 expression.
A limited change of proliferation but a substantial effect in migration was measured in MACC1+ clones: proliferation: FLO1: CTRL vs. MACC1 +18.42% (p = 0.010); OE33: shCTRL vs. shMACC1 – 12.89% (p = 0.346); migration: FLO1: CTRL vs. MACC1 +208.6% (p = 0.004); OE33: shCTRL vs. shMACC1 – 58.81% (p = 0.013).
Treatment with AZD6244 led to a reduction of migration only in endogenously or ectopically MACC1 + cells: FLO1: CTRL + 27.5% (p = 0.025) MACC1+ –67.7% (p < 0.001); OE33: CRTL: – 81.3% (p = 0.001), shMACC1 – 15.1% (p = 0.25).
In vivo, the group of FLO1/MACC1 mice (n = 7) developed larger liver metastasis after 16 days (liver weight: mean 4.04 g CTRL vs. 5.29 g MACC1+; p = 0.040). Treatment with AZD6244 led to a reduced liver metastasis only in the MACC1+ group: MACC1+: -86.9% (p = 0.002) CTRL- < 0.01% (p = 0.217).
In patients MACC1 expression was associated with a poor prognosis (median OS 64.8 vs. 31.2 months; p < 0.0001). The multivariate Cox-Regression model showed that MACC1 is an independent prognostic marker in AGE/S patients (HR 1.51, CI-95: 1.01 – 2.26; p = 0.043).
MACC1 is anenhancer of tumor aggressiveness and a predictor of poor survival in AGE/S. The inhibition of MACC1 seems to be a promising therapy option for those tumors.