Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
Mol Cancer Res. 2022 Aug 5;20(8):1305-1319. doi: 10.1158/1541-7786.MCR-21-0994.
KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 (ITGB4) specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6β4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate.
Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.
结直肠癌中的 KRAS 突变通过增加侵袭性和更高的肺转移率与侵袭性肿瘤行为相关，但这些特征背后的生物学机制尚不完全清楚。在这项研究中，我们表明 KRAS 突变型结直肠癌通过 ERK/MEK 信号通路上调整合素 α6β4。特异性敲除整合素β4（ITGB4）会耗尽整合素 α6β4 的表达，从而降低癌细胞的侵袭和迁移能力。我们还观察到，与注射 ITGB4 野生型 KRAS 突变型结直肠癌细胞的小鼠相比，注射 ITGB4 敲除 KRAS 突变型结直肠癌细胞的小鼠肺部转移灶的数量和面积减少，而肝脏转移没有差异。抑制 KRAS 突变型结直肠癌中的整合素 α6β4 可能是减少 KRAS 侵袭表型和相关肺转移率的潜在治疗靶点。
敲除 ITGB4，其在 KRAS 突变型结直肠癌中过度表达并促进肿瘤侵袭性，可降低局部侵袭性和肺转移率。
