Abstract. Nicotine as a cigarette component is an established risk factor for colorectal cancer tumorigenesis. The downstream signaling pathways of nicotinic acetylcholine receptors (nAchRs) are believed to be responsible for the cellular effects. In the present study, we evaluated the effects and novel mechanisms for nicotine on the capacity for colorectal cancer cell invasion and metastasis. LOVO and SW620 colorectal cancer cells were stimulated with nicotine in vitro. A Transwell chamber model was applied to detect the capacity for tumor cell invasion. Assays for gelatin zymography and western blotting were applied to detect the activity and expression of metastasis-related matrix metalloproteinases (MMPs), respectively. Signal transduction was assessed by immunoblotting for the phosphorylation of relevant signal molecules and the application of pharmaceutical inhibitors. We showed that nicotine increased LOVO and SW620 colorectal cancer cell invasion along with enhanced activity and expression of MMP-1, -2 and -9. Nicotine increased phosphorylation of p38, ERK, Akt and PI3K p85 but had no effect on phosphorylation of JNK, or NF-κB. Of the pharmaceutical inhibitors of U0126 (ERK1/2 inhibitor), LY294002 (Akt activation inhibitor), SB239063 (p38 MAPK activation inhibitor) and hexamethonium (Hex) (nAchRs inhibitor), the cellular and molecular effects were reduced by the applications of SB239063 and Hex. We concluded that nicotine stimulates the invasion and metastasis of colon cancer cells in vitro via activation of the nAchRs and the p38 MAPK downstream signaling pathway. Therefore, p38 MAPK may have potential as a therapeutic target for smoking-related human colorectal cancer metastasis.

Caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea is known to induce mitochondrial dysfunctions. In this study, the anticancer property of caulerpin was assessed in a panel of colorectal cancer cell lines. We demonstrated that caulerpin inhibited oxidative phosphorylation (OXPHOS) and facilitated an early intervention of the mitochondrial function, via inhibiting mitochondrial complex I, accompanied by the dissipation of mitochondrial membrane potential and a surge of reactive oxygen species (ROS) generation. Moreover, in response to the increment in AMP/ATP ratio, the energy sensor AMP-activated protein kinase (AMPK) was activated by caulerpin treatment in a calcium/calmodulin-dependent protein kinase 2 (CaMKK2)‑dependent manner. Distinguished effect on glycolysis was observed at different time-points after caulerpin treatment. Glycolysis was enhanced after a short time treatment with caulerpin, associated with upregulation of glucose transporter 1 (GLUT1), hexokinase II (HKII) and 6-phosphofructo-2-kinase (PFKFB3) protein expressions. However, long-term activation of AMPK by caulerpin damaged the glycolysis and glucose metabolism in colorectal cells, finally causing cell death. The persistent effect of caulerpin was mediated by AMPKα1, rather than AMPKα2, to abolish cell viability through hindering mTORC1-4E-BP1 axis. Moreover, caulerpin synergized with the glycolytic inhibitor 3BP in inhibiting cellular proliferation both in vitro and in vivo. Our findings on the previously uncharacterized anticancer effects of caulerpin may provide potential therapeutic approaches targeting the colorectal carcinoma metabolism.

No abstract

Background: Hepatocellular carcinoma (HCC) is a malignant tumor with frequent intrahepatic metastases; extrahepatic metastases are not rare but less frequent compared to intrahepatic ones. The most frequent sites of extrahepatic metastases are the lungs, followed by the lymph nodes, bones, and adrenal glands. Case report covering gastrointestinal (GI) tract involvement from HCC is limited. Case presentation: A 60-year-old man was referred to us in May 2019 with a diagnosis of sigmoid colon tumor. The patient had a history of HCC and had received two stages of open resections for the primary and the abdominal metastasis successively and many times of transcatheter arterial chemoembolization (TACE). The sigmoid colon tumor received Hartmann procedure after abdominal enhanced computerized tomography (CT) scan and colonoscopy, while postoperative pathology and immunohistochemistry identified it as extrahepatic colonic metastasis from HCC. Conclusions: The ratio of extrahepatic metastasis to the digestive tract was very low, and the majority was upper gastrointestinal involvement because of direct invasion or intraperitoneal implantation. TACE may be the risk factor of retrograde hematogenous metastasis to the downstream colon.