Park Ga Bin, Choi Sangbong, Yoon Yoo Sang, Kim Daejin
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
Department of Internal Medicine, Division of Respirology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul 01757, Republic of Korea.
Mol Med Rep. 2021 Jun;23(6). doi: 10.3892/mmr.2021.12062. Epub 2021 Apr 13.
The abnormal expression of tropomyosin receptor kinase (Trk) serves an important role in the promotion of cancer progression. Homeobox C6 (HOXC6) and A disintegrin and metalloproteinase domain‑containing 8 (ADAM8) are associated with the invasiveness of cancer cells. However, the exact relationship between these molecules and their downstream signaling pathways in chemoresistant colon cancer cells are largely unknown. Therefore, the current study investigated the association between TrkB/C with HOXC6 and ADAM8 in the induction of drug‑resistant colon cancer cell metastasis. The results demonstrated that chemoresistant colon cancer cells exhibited upregulated TrkB/C, HOXC6 and ADAM8 expression. Additionally, but also chemoresistant colon cancer cells demonstrated higher migratory activities compared with parent colon cancer cells. The pharmacological inhibition of TrkB/C activity reduced the phosphorylation of mitogen‑activated protein kinase kinase/ERK and subsequently suppressed HOXC6 and ADAM8 expression. In addition, gene silencing of inhibited ADAM8 and MMP activity, and inhibited the migration and invasion of drug‑resistant cancer cells. However, the targeted downregulation of ADAM8 using small interfering RNA failed to suppress TrkB/C‑associated ERK‑mediated HOXC6 signaling activity. Furthermore, pre‑treatment with ADAM10‑ and ADAM17‑specific inhibitors had no effect on attenuating the invasiveness of chemoresistant colon cancer cells. The results indicated that TrkB/C‑mediated ERK activation serves an important role in the metastasis of drug‑resistant colon cancer cells through the regulation of HOXC6/ADAM8 activity.
原肌球蛋白受体激酶（Trk）的异常表达在促进癌症进展中起重要作用。同源盒C6（HOXC6）和含解整合素和金属蛋白酶结构域8（ADAM8）与癌细胞的侵袭性相关。然而，这些分子与其在化疗耐药结肠癌细胞中的下游信号通路之间的确切关系在很大程度上尚不清楚。因此，本研究调查了TrkB/C与HOXC6和ADAM8在诱导耐药结肠癌细胞转移中的关联。结果表明，化疗耐药结肠癌细胞表现出TrkB/C、HOXC6和ADAM8表达上调。此外，化疗耐药结肠癌细胞相比亲本结肠癌细胞还表现出更高的迁移活性。TrkB/C活性的药理学抑制降低了丝裂原活化蛋白激酶激酶/ERK的磷酸化，随后抑制了HOXC6和ADAM8的表达。此外，ADAM8基因沉默抑制了ADAM8和基质金属蛋白酶活性，并抑制了耐药癌细胞的迁移和侵袭。然而，使用小干扰RNA靶向下调ADAM8未能抑制TrkB/C相关的ERK介导的HOXC6信号活性。此外，用ADAM10和ADAM17特异性抑制剂预处理对减弱化疗耐药结肠癌细胞的侵袭性没有影响。结果表明，TrkB/C介导的ERK激活通过调节HOXC6/ADAM8活性在耐药结肠癌细胞的转移中起重要作用。
