Department of Gastroenterology, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China.
Department of Gastroenterology, Wuhan University Affiliated Zhongshan Hospital, Wuhan, Hubei 430032, P.R. China.
Oncol Rep. 2019 Feb;41(2):1035-1044. doi: 10.3892/or.2018.6877. Epub 2018 Nov 21.
The occurrence of colorectal cancer (CRC) is associated with a variety of oncogenes and tumor‑suppressor genes. As a tumor‑suppressor gene, the liver kinase B1 gene (LKB1, also known as serine/threonine kinase 11, STK11) is closely related to tumor angiogenesis, invasion and metastasis, but its molecular mechanisms remain unclear. The aim of the present study was to investigate the effects of LKB1 on the invasion and metastasis of CRC, and to explore its molecular mechanisms. By detecting the expression of LKB1 in CRC, we can provide a reference index for diagnosing the depth of invasion and lymph node metastasis. Immunohistochemistry results indicated that LKB1 expression was strongly positive in normal colon tissue and that it inhibited the production of CRC. Immunocytochemical staining showed that the expression of LKB1 was significantly decreased in adenocarcinoma and mucinous adenocarcinoma tissues, and this reduced expression induced the invasion and metastasis of CRC. In the present study, LKB1 small interfering RNA (LKB1 siRNA) was transfected into LoVo cells to observe the effect of LKB1 on the invasion and metastasis of CRC. LKB1 silencing decreased the phosphorylation of AMP‑activated protein kinase (p‑AMPK) in its downstream pathway, which increased the phosphorylation of protein kinase B (p‑AKT) and promoted tumor cell proliferation, enhancing the migration and invasion of CRC. The present study also explored the role of metformin in the LKB1 signaling pathway. Metformin inhibits the invasion and metastasis of CRC by activating p‑AMPK, thereby inhibiting the activation of p‑AKT. These results suggest that LKB1 plays an important role in the invasion and metastasis of CRC by activating AMPK, negatively regulating the AKT signaling pathway and regulating gene expression. Mutation or deletion of LKB1 is expected to be a novel therapeutic target or clinical biomarker for the prevention of the invasion and metastasis of CRC.
结直肠癌（CRC）的发生与多种癌基因和抑癌基因有关。肝激酶 B1 基因（LKB1，也称为丝氨酸/苏氨酸激酶 11，STK11）作为一种抑癌基因，与肿瘤血管生成、侵袭和转移密切相关，但分子机制尚不清楚。本研究旨在探讨 LKB1 对 CRC 侵袭和转移的影响，并探讨其分子机制。通过检测 CRC 中 LKB1 的表达，可为诊断浸润深度和淋巴结转移提供参考指标。免疫组化结果表明，LKB1 在正常结肠组织中表达呈强阳性，抑制 CRC 的产生。免疫细胞化学染色显示，LKB1 在腺癌和黏液性腺癌组织中的表达明显降低，这种表达的降低诱导了 CRC 的侵袭和转移。本研究将 LKB1 小干扰 RNA（LKB1 siRNA）转染入 LoVo 细胞，观察 LKB1 对 CRC 侵袭和转移的影响。LKB1 沉默降低了其下游通路中 AMP 激活蛋白激酶（p-AMPK）的磷酸化，增加了蛋白激酶 B（p-AKT）的磷酸化，促进肿瘤细胞增殖，增强 CRC 的迁移和侵袭。本研究还探讨了二甲双胍在 LKB1 信号通路中的作用。二甲双胍通过激活 p-AMPK 抑制 CRC 的侵袭和转移，从而抑制 p-AKT 的激活。这些结果表明，LKB1 通过激活 AMPK 在 CRC 的侵袭和转移中发挥重要作用，负调控 AKT 信号通路，调节基因表达。LKB1 的突变或缺失有望成为预防 CRC 侵袭和转移的新的治疗靶点或临床生物标志物。
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