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Hexokinase 1 (HK1) has been implicated in tumorigenesis. However, its role in tumor metastasis and progression has not been evaluated. The aim of this study is to evaluate the role of HK1 in the metastasis in CRC. Methods: The expression level of HK1 was detected using quantitative RT-PCR and western blot in 9 CRC cell lines and 1 human colon epithelial cell line NCM460 (Figure 1A). HK1 was overexpressed via lentiviral vector system and silenced using specific small interference RNA (si-HK1) in DLD1 and HCT8. Then wound-healing, migration assay and invasion assay were carried out to investigate the function of HK1 in CRC cells. RT-PCR and Western blot was performed to detect the change of Snail2 following the up-regulated expression of HK1. Results: HK1 expression was overexpressed by HK1-cDNA and was inhibited by si-HK1 in DLD1 and HCT8 (Figure 1B and 1C). Ectopic expression of HK1 promoted cell migration and invasion in CRC cells and promoted lung metastasis in mouse models (Figure 1D). Furthermore, HK1 induced migration and invasion in CRC cells was found to activate expression of Snail2 and in turn, induce epithelial-mesenchymal transition (EMT) and cancer progression (Figure 1E). Conclusions: High expression of HK1 could activate expression of Snail2 and in turn, induce EMT. Our findings suggest that HK1 may be a potential prognostic biomarker and therapeutic target for CRC invasion and metastasis. Keywords: Colorectal Cancer, HK1, Migration, Invasion Figure 1. A. The expression level of HK1 in 10 cell lines. B, C. HK1 expression was overexpressed by HK1-cDNA and was inhibited by si-HK1 in DLD1 and HCT8. *P< 0.05. D. Overexpression of HK1 in HCT8 increased the capacity of cell migration and invasion in vitro and in vivo. E. Expression levels of Snail2 and EMT were induced after HK1 overexpression. Citation Format: Xiaobin Zheng, Huashan Liu, Xiaoli Zhong, Xuanhui Liu, Zerong Cai, Yufeng Chen, Xiaosheng He, Ping Lan, Xiaojian Wu. HK1 induces epithelial-mesenchymal transition and promotes metastasis of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2840.

Introduction: Early-onset colorectal cancer (CRC), as defined by CRC diagnosed before age 50, has been increasing in the past 2 decades, with unidentified reasons. Type 2 diabetes increases risk of CRC with average age of onset, however, epidemiological data linking type 2 diabetes and risk of early-onset CRC is thus far limited. Methods: To examine the association between type 2 diabetes and risk of early-onset CRC, we conducted a nested case-control study of early-onset CRC among participants aged 18-50 years with at least 2 years and 3 months of continuous enrollment in the IBM® MarketScan® Research Databases (2006-2015), the largest database that covers healthcare claims from over 150 million privately insured adults in the US. Incident CRC cases were identified using ICD-9-CM diagnosis codes on pathologists' claims. For cases, the index dates were set at the first pathologist date. Controls without CRC were identified using 1:8 frequency matching on age, sex, and geographical region, duration of insurance enrollment, and Rx coverage. Type 2 diabetes within 2 years of the index dates were identified through the ICD-9-CM and confirmed by Klabunde algorithm. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 5986 early-onset CRC cases were identified. Type 2 diabetes was significantly associated with an increased risk of early-onset CRC (prevalence in cases/controls: 7.2% vs 4.3%; OR: 1.40, 95% CI 1.24-1.56), after adjusting for the matching factors, health care utilization, Charlson Comorbidity Index, obesity, inflammatory bowel disease (IBD), colonoscopy and fecal occult blood test (FOBT), and family history of gastrointestinal neoplasm. Notably, the association between type 2 diabetes and early onset-CRC was similar for colon (OR: 1.44, 95% CI 1.25-1.64) and rectal cancer (OR: 1.30, 95% CI 1.18-1.56) (Pheterogeneity = 0.41). These associations remain similar while we restricted the analyses to individuals without IBD, endoscopy/FOBT, or early symptoms, respectively. In addition, the findings were also similar for women and men, as well as CRC diagnosed before and after age 45. Conclusions: Type 2 diabetes was associated with increased risk of early-onset CRC with similar strength of associations for colon and rectal cancer. Citation Format: Zitong Li, Xiaobin Zheng, Katelin B. Nickel, Hanyu Chen, Andrew Tipping, Long H. Nguyen, Andrew T. Chan, Ryan C. Fields, Nicholas O. Davidson, Edward Giovannucci, Margaret A. Olsen, Peter T. Campbell, Graham A. Colditz, Yin Cao. Diabetes and risk of early-onset colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2351.

Background and Aim: Engulfment and cell motility 1 (ELMO1) has been linked to the invasive phenotype of various types of cancer cells such as glioma cells, rhabdomyosarcoma cells, ovarian cancer cells and so on. However, the biological functions of ELMO1 in colorectal cancer (CRC) cells remains unclear. The aim of this study is to evaluate the role of ELMO1 in the metastasis in CRC. Methods: The expression level of ELMO1 was detected using quantitative RT-PCR and western blot in 9 CRC cell lines and 1 human colon epithelial cell line NCM460. ELMO1 was overexpressed via lentiviral vector system and silenced using specific small interference RNA (si-ELMO1) in HCT116 and SW620. Then wound-healing, migration assay and invasion assay were carried out to investigate the function of ELMO1 in CRC cells. Western blot was performed to detect the change of signaling molecule extracellular signal-regulated kinase 1/2 (ERK1/2) following the down-regulated or up-regulated expression of ELMO1. Results: ELMO1 expression was inhibited by si-ELMO1 and was overexpressed by ELMO1-cDNA in HCT116 and SW620. Ectopic expression of ELMO1 in HCT116 and SW620 was shown to promote migration and invasion, while inhibited ELMO1 expression suppressed the capacity of cell migration and invasion. Furthermore, ELMO1 induced migration and invasion in CRC cells was found to be associated with the activation of MAPK/ERK pathway. Conclusions: High expression of ELMO1 was found to be associated with the metastasis via the activation of MAPK/ERK signaling pathway. This finding provides a molecular basis for the role of ELMO1 in the progression of CRC, which may suggest a novel target for the treatment of CRC. Citation Format: Xiao-bin Zheng, Chi Zhou, Hai-chun Cheng, Tuo Hu, Hua-shan Liu, Xuan-hui Liu, Xian-rui Wu, Feng-wei Wang, Yu-feng Chen, Jian-ping Wang, Xiao-sheng He, Ping Lan. ELMO1 promotes metastasis in colorectal cancer cells via activation of MAPK/ERK signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4849. doi:10.1158/1538-7445.AM2017-4849

Background and Aim: A number of studies demonstrated that CD47 was overexpressed in several kinds of tumors including colorectal cancer (CRC). Furthermore, the level of CD47 was positively correlated with tumor proliferation, stemness and metastasis. The aim of this study is to evaluate the role of CD47 in the metastasis and proliferation in CRC. Methods: We used the data from GEO database GSE8671 to analyze the expression level of CD47 and its relationship with prognosis in CRC. The expression levels of CD47 in normal and CRC tissues from our hospital were detected using quantitative RT-PCR and western blot. CD47 was downregulated or overexpressed via lentiviral vector system. Then the RTCA assay and migration assay were carried out to investigate the function of CD47 in cell proliferation and migration. Western blot for cancer related pathways was performed to find out the downstream signaling pathways of CD47. Results: Increased expression of CD47 was found in CRC tissues. Inhibition of CD47 expression in HCT116 by ShRNA attenuated the capacity of cell proliferation and migration. On the other hand, overexpression of CD47 in DLD1 increased the capacity for cell proliferation and migration. CD47 induced cell proliferation and migration was found to be associated with the activation of MAPK/ERK pathway. Conclusions: High expression of CD47 was found to be associated with the proliferation and metastasis in CRC via the activation of MAPK/ERK signaling pathway. These findings provide an SIRPα-independent mechanism for CD47 in the progression of CRC, which may find a novel therapy target for the precise treatment of CRC. Citation Format: Tuo Hu, Yu-feng Chen, Chi Zhou, Jia Ke, Hua-shan Liu, Xiao-bin Zheng, Jian-ping Wang, Xiao-jian Wu, Xian-rui Wu, Ping Lan. CD47 promotes metastasis and proliferation of colorectal cancer via MAPK/ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4866. doi:10.1158/1538-7445.AM2017-4866

Background and aim: Our previous study showed that high expression of CD73 (ecto-5’-nucleotidase) was a poor prognostic biomarker in patients with colorectal cancer (CRC). However, the underlying mechanism is unclear. Metastasis and chemo-resistance are among the main causes for the poor outcomes of CRC. The aim of this study is to evaluate the role of CD73 in the metastasis and chemo-resistance in CRC. Methods: The expression levels of CD73 were detected using quantitative RT-PCR and Western blot in 9 CRC cell lines and 3 5-FU-resistant cell lines (HCT8-FR, HCT116-FR, and RKO-FR). CD73 was overexpressed via lentiviral vector system and silenced using specific small interference RNA (si-CD73) in HCT8 and RKO. We then performed migration, invasion and MTS assays and wound healing assessment to evaluate the function of CD73 in cell progression and chemo-resistance. We conducted Cignal Finder Reporter Array to assess the main downstream signaling pathways of CD73. Results: Increased expression of CD73 was found in all 3 5-FU-resistant cell lines. Inhibition of CD73 expression in HCT8 and RKO by si-CD73 attenuated the capacity of cell migration and invasion but increased the sensitivity to 5-FU. On the other hand, overexpression of CD73 in HCT8 and RKO increased the capacity for cell migration but decreased the sensitivity to 5-FU. CD73-induced migration and chemo-resistance was found to be associated with the activation of MAPK/ERK pathway. Conclusions: High expression of CD73 was found to be associated with the metastasis and resistance to 5-FU via the activation of MAPK/ERK signaling pathway. This finding provides a molecular basis for the role of CD73 in the progression of CRC, suggesting a novel target for the treatment of CRC. Citation Format: Xuan-hui Liu, Xian-rui Wu, Yu-feng Chen, Feng-wei Wang, Xiao-bin Zheng, Dan Xie, Bo Shen, Jian-ping Wang, Xiao-jian Wu, Ping Lan. Role of CD73 in promoting metastasis and resistance to 5-fluorouracil of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2938.