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.
This study aim is to enhance the understanding, diagnosis and treatment of desmoplastic small round cell tumor (DSRCT) and to determine what factors can affect survival of the disease in China. We report here 8 patients with DSRCT in our center who received a variety of treatment methods. By reviewing the literature published from Chinese database (CNKI, WANGFAN, VIP, CBM, CMCC) in 2000 to 2015 with the terms of “dsrct”, “desmoplastic” and “small round-cell tumor”,104 eligible cases of DSRCT(including 8 cases in our hospital) were retrospectively analyzed. Among the 104 patients, Median age was 24 years with a range of 15 to 54 years. The main primary tumor site was the abdomen and/or pelvis in 92/104 patients (88.5%). Only 25% of patients had localized disease. Most of the patients had received adjuvant chemotherapy (87.5%) and 76.9% patients had not experienced adjuvant radiotherapy. One-fourth of the patients underwent grossly complete surgical resection, and 33.7% and 41.3% patients received no surgery and incomplete surgical resection, respectively. Median overall survival for all patients was 26 months (95% CI: 20.29–31.71). Multivariate analysis revealed that Metastatic status (HR: 2.327, 95% CI: 1.136–4.768, P = .021), Surgical patterns (HR: 0.673, 95% CI: 0.487–0.928, P = .016), and Adjuvant chemotherapy (HR: 0.337, 95% CI: 0.167–0.678, P = .002) were significant independent prognostic factors for longer overall survival. It was noteworthy that CD99 were significantly associated with OS ( P = .002). Here, we identified the prognostic factors which may facilitate risk-adapted treatments for this rare DSRCT group, which should be further investigated.
Considerable evidence has implied that α7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. The aim of the present study was to determine the role of endogenous α7nAChR signaling in tumor-associated macrophages (TAMs) in human colorectal cancer (CRC) metastasis and prognosis. α7nAChR expression in primary tumor cells and adjacent stroma cells especially in TAMs in 51 CRC patients was observed. Using a human monocyte THP-derived macrophages (TMs) with α7nAChR-siRNA knockdown (TMα7−/−) and a CRC cell Transwell co-culture model, the migration and invasion of two CRC cells, LoVo and SW620, were determined. Western blotting was carried out to investigate the expression of multiple molecules involved in the NF-κB, STAT3, PI3K signaling pathways in mimic TAMs, i.e., TMs exposed to in-direct LoVo cell stimulation. A nicotinic α7 receptor antagonist [α-bungarotoxin (α-Btx)] and three pharmaceutical inhibitors: AG490 (JAK2/STAT3 inhibitor), LY294002 (PI3K inhibitor) and Bay 11–7082 (NF-κB inhibitor) were applied to evaluate whether these signaling pathways were associated with the enhanced migration of CRC cells when co-cultured with α7nAChR knockdown TMs. The results revealed that the expression of α7nAChR in TAMs differed in patients. However, CRC patients who had a high incidence of hepatic metastasis showed no or low expression of α7nAChR in TAMs. TMs with α7nAChR-siRNA knockdown (TMα7−/−) significantly enhanced the migration and invasion of the two CRC cell lines LoVo and SW620. α7nAChR knockdown in TMs significantly downregulated phosphorylation of STAT3, PI3K p85 and NF-κB p65 after co-culturing with LoVo cells. Inhibition of JAK2/STAT3 prevented the TMα7−/−-enhanced migration of LoVo cells. α7nAChR expressed in TAMs in human CRC patients plays an important role in preventing metastasis and could be a prognostic marker in CRCs, which may be regulated by the JAK2/STAT3 signaling pathway.
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