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Colorectal cancers (CRCs) is the most commonly diagnosed and deadly cancer types in the world. Despite advances in chemotherapy for CRCs, drug resistance remains a major challenge to high incurable and eventually deadly rates for patients. CPT-11 is one of the current chemotherapy agents for CRC patients and the CPT-11 resistance development of CRCs is also inevitable. Recently, accumulating data has suggested that DNA repair system might be an inducer of chemotherapy resistance in cancer cells. Thus, this study was aimed to examine whether MutS homolog (MSH) 2, one member of DNA repair system, plays a role to affect the cytotoxicity of CPT-11 to CRCs. Human DLD-1 CRC cells were used in this study. It was shown that MSH2 gene and protein expression could be upregulated in DLD-1 cells under CPT-11 treatment and this upregulation subsequently attenuates the sensitivity of DLD-1 cells to CPT-11. Moreover, ERK1/2 and Akt signaling and AP-1 transcription factor have been found to modulate these effects. These results elucidate the drug resistance role of MSH2 upregulation in the CPT-11-treated DLD-1 CRC cells. Our findings may provide a useful thought for new adjuvant drug development by controlling the DNA repair system., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Many colorectal cancer (CRC) patients report having Oxaliplatin-induced peripheral neuropathy (OXAIPN), compromising their overall quality of life (QoL). Yet, the existing studies on examining the effects of elastic-band resistance exercise yielded inconsistent results and there was a scare study with CRC population employing a longitudinal research design. The purpose of this non-randomized preliminary study was to examine the effects of an educational program providing skills and knowledge about OXAIPN along with home-based lower extremity elastic-band exercise training in a sample (n = 42) of Taiwanese patients with CRC., Method: A quasi-experimental study with one-group, pretest-posttest repeated measures and longitudinal design was employed. The 4.5-month interventional protocol included 8 sessions of face-to-face education from the 3rd to the 7th cycles of chemotherapy. Physical exams, muscle strength and endurance, and self-reports regarding adverse impacts of OXAIPN and QoL were obtained at three time points throughout chemotherapy course., Results: The most consistently significant increase was the participants' muscle strength and endurance measured with one-repetition maximum and 6-min walk distance, respectively (both P < .001). The participants' OXAIPN-related QoL showed significant improvements at some time points of the chemotherapy cycles, but not others., Conclusion: Study findings indicated that an educational program combined with knowledge about OXAIPN symptom management and skills with lower extremity resistance training had potential benefits over time on muscle strength and endurance and autonomic dimension of CIPN-related QoL. These preliminarily results may assist healthcare providers to incorporate self-management strategies such as lower extremity exercise for patients with OXAIPN to partially mitigate its negative effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the longitudinal incidence, severity, pattern of changes or predictors of oxaliplatin-induced peripheral neuropathy (OXAIPN) in Taiwanese patients with colorectal cancer. A longitudinal repeated measures study design was employed, and 77 participants were recruited from the colorectal and oncology departments of two teaching medical centres in Taiwan. Physical examinations were performed, and self-reports regarding adverse impacts of OXAIPN and quality of life were obtained at five time points throughout 12 cycles of chemotherapy (C/T). The incidence of OXAIPN increased with C/T cycles (31.1%-81.9%), and the upper limb numbness and cold sensitivity were most significant acute OXAIPN symptoms (29.9%-73.6%). Findings also documented significant increases in overall severity, symptom distress, interference and physical results associated with OXAIPN over the course of C/T. Predictors of OXAIPN severity varied by treatment cycle, including younger patient, higher cumulative dose of oxaliplatin, greater body surface area, receipt of chemotherapy in winter and the occurrence of OXAIPN during prior C/T cycles. The results from this study might help healthcare providers to recognise the symptom characteristics, degree of influences, trends and high-risk group of OXAIPN, facilitating early evaluation and potential interventions to mitigate or prevent negative effects of OXAIPN on patients., (© 2018 John Wiley & Sons Ltd.)

Colorectal cancer (CRC) is the fourth most common cause of cancer death worldwide. Chemotherapy has been the major strategy for treating patients with advanced CRC. Oxaliplatin (OXA) is used as both an adjuvant and neoadjuvant anticancer agent available to treat advanced CRC. High-mobility group box 1 protein (HMGB1) is a critical regulator of cell death and survival. HMGB1 overexpression has been shown to be resistant to cytotoxic agents. In addition, Metformin, a widely used drug for diabetes, has emerged as a potential anticancer agent. In this study, we examined whether HMGB1 plays a role in the OXA- and/or metformin-induced cytotoxic effect on CRC cells. The results showed that treatment with OXA increased HMGB1 expression in the ERK1/2- and Akt-dependent manners in DLD-1 cells. HMGB1 gene knockdown enhanced the cytotoxicity and cell growth inhibition of OXA. Moreover, OXA-increased HMGB1 expression was by inducing NF-κB-DNA-binding activity to in DLD-1 cells. Compared to a single agent, OXA combined with metformin administration resulted in cytotoxicity and cell growth inhibition synergistically, accompanied with reduced HMGB1 level. These findings may have implications for the rational design of future drug regimens incorporating OXA and metformin for the treatment of CRC., (© 2018 Wiley Periodicals, Inc.)

Hypomagnesemia is a recognized side-effect of cetuximab- or panitumumab-based chemotherapy for metastatic colorectal cancer (mCRC). The clinical relevance of hypomagnesemia is under debate. Thus, a systematic review and meta-analysis of retrospective studies and randomized clinical trials (RCTs) comparing hypomagnesemia with normal magnesium levels in wild-type KRAS mCRC was performed. One RCT, two retrospective studies, and two American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) conference presentations from phase III RCTs involving 1723 patients were included in this study. Patients with hypomagnesemia demonstrated better progression-free survival (PFS) (Hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.47-0.88), overall survival (OS) (HR: 0.72; 95% CI: 0.53-0.92), and objective response rate (ORR) (Risk ratio [RR]: 1.81; 95% confidence interval [CI]: 1.30-2.52). By subgroup analysis, frontline, later lines or combination therapy with hypomagnesemia were associated with PFS benefits (HR: 0.78; 95% CI: 0.62-0.98; HR: 0.60; 95% CI: 0.40-0.90; HR: 0.62; 95% CI: 0.41-0.94, respectively). In patients with wild-type KRAS mCRC, hypomagnesemia is associated with better clinical benefits of PFS, OS and ORR when treated with cetuximab- or panitumumab-based chemotherapy. Future clinical trials should corroborate its predictive role.

Background/aims: Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related deaths worldwide. PRDXs are antioxidant enzymes that play an important role in cell differentiation, proliferation and apoptosis and have diverse functions in malignancy development. However, the mechanism of aberrant overexpression of PRDX6 in CRC remains unclear., Methods: Boyden chamber assay, flow cytometry and a lentiviral shRNA targeting PRDX6 and transient transfection with pCMV-6-PRDX6 plasmid were used to examine the role of PRDX6 in the proliferation capacity and invasiveness of CRC cells. Immunohistochemistry (IHC) with tissue array containing 40 paraffin- embedded CRC tissue specimens and Western blot assays were used to detect target proteins., Results: PRDX6 was significantly up-expressed in different comparisons of metastasis of colorectal adenomas in node-positive CRC (P = 0.03). In in vitro HCT-116, PRDX6 silencing markedly suppressed CRC cell migration and invasiveness while also inducing cell cycle arrest as well as the generation of reactive oxygen species (ROS); specific overexpression of PRDX6 had the opposite effect. Mechanistically, the PRDX6 inactivation displayed decreased levels of PRDX6, N-cadherin, β-catenin, Vimentin, Slug, Snail and Twist-1 through the activation of the PI3K/ AKT/p38/p50 pathways, but they were also significantly inhibited by PRDX6 transfectants. There was also increased transcriptional activation of dimethylation of histone H3 lysine 4 (H3K4me3) of PRDX6 promoter via the activation of the PI3K/Akt/NFkB pathways., Conclusion: Our findings demonstrated that PRDX6 expression plays a characteristic growth-promoting role in CRC metastasis. This study suggests that PRDX6 may serve as a biomarker of node-positive status and may have a role as an important endogenous regulator of cancer cell tumorigenicity in CRC. PRDX6 may also be an effective therapeutic target., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Colorectal cancer (CRC) is one of the leading causes of cancer mortality and 5-Fluorouracil (5-FU) is the most common chemotherapy agent of CRC. A high level of X-ray repair cross complementing group 1 (XRCC1) in cancer cells has been associated with the drug resistance occurrence. Moreover, the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been indicated to regulate the cancer cell survival. Thus, this study was aimed to examine whether XRCC1 plays a role in the 5-FU/AMPK agonist (AICAR)-induced cytotoxic effect on CRC and the underlying mechanisms. Human HCT-116 colorectal cells were used in this study. It was shown that 5-FU increases the XRCC1 expression in HCT-116 cells and then affects the cell survival through CXCR4/Akt signaling. Moreover, 5-FU combined with AICAR further result in more survival inhibition in HCT-116 cells, accompanied with reduced CXCR4/Akt signaling activity and XRCC1 expression. These results elucidate the role and mechanism of XRCC1 in the drug resistance of HCT-116 cells to 5-FU. We also demonstrate the synergistic inhibitory effect of AMPK on 5-FU-inhibited HCT-116 cell survival under the 5-FU and AICAR co-treatment. Thus, our findings may provide a new notion for the future drug regimen incorporating 5-FU and AMPK agonists for the CRC treatment., Competing Interests: The authors declare no conflicts of interest.

Erinacine A, a major active component of a diterpenoid derivative isolated from Hericium erinaceus mycelium, has been demonstrated to exert anticancer effects. Herein, we present an investigation of the molecular mechanism of erinacine A induction associated with cancer cells' aggressive status and death. A proteomic approach was used to purify and identify the differentially expressed proteins following erinacine A treatment and the mechanism of its action in apoptotic and the targets of erinacine A. Our results demonstrate that erinacine A treatment of HCT-116 and DLD-1 cells increased cell cytotoxicity and reactive oxygen species (ROS) production as well as decreased cell proliferation and invasiveness. Ten differentially displayed proteins were determined and validated in vitro and in vivo between the erinacine A-treated and untreated groups. In addition, erinacine A time-dependent induction of cell death and inhibitory invasiveness was associated with sustained phosphorylation of the PI3K/mTOR/p70S6K and ROCK1/LIMK2/Cofilin pathways. Furthermore, we demonstrated that erinacine A-induced HCT-116 and DLD-1 cells viability and anti-invasion properties by up-regulating the activation of PI3K/mTOR/p70S6K and production of ROS. Experiments involving specific inhibitors demonstrated that the differential expression of cofilin-1 (COFL1) and profilin-1 (PROF1) during erinacine A treatment could be involved in the mechanisms of HCT-116 and DLD-1 cells death and decreased aggressiveness, which occurred via ROCK1/LIMK2/Cofilin expression, with activation of the PI3K/mTOR/p70S6K signalling pathway. These findings elucidate the mechanism of erinacine A inhibiting the aggressive status of cells by activating PI3K/mTOR/p70S6K downstream signalling and the novel protein targets COF1 and PROF1; this could be a good molecular strategy to limit the aggressiveness of CRC cells., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is a well-known, major active agent of the alkaloid derivative of Camptotheca acuminata with valuable biological properties, including anti-tumorigenic activity. In this study, we investigated the molecular mechanisms by which CIL-102 mediated the induction of cell death, and we performed cell cycle G2/M arrest to clarify molecular changes in colorectal cancer cells (CRC). Treatment of DLD-1 cells with CIL-102 resulted in triggering the extrinsic apoptosis pathway through the activation of Fas-L, caspase-8 and the induction of Bid cleavage and cytochrome c release in a time-dependent manner. In addition, CIL-102 mediated apoptosis and G2/M arrest by phosphorylation of the Jun N-terminus kinase (JNK1/2) signaling pathway. This resulted in the expression of NFκB p50, p300 and CREB-binding protein (CBP) levels, and in the induction of p21 and GADD45 as well as the decreased association of cdc2/cyclin B. Furthermore, treatment with the JNK1/2 (SP600125), NFκB (PDTI) or the p300/CBP (C646) inhibitors abolished CIL-102-induced cell cycle G2/M arrest and reversed the association of cdc2 with cyclin B. Therefore, we demonstrated that there was an increase in the cellular levels of p21 and GADD45 by CIL-102 reduction in cell viability and cell cycle arrest via the activation of the JNK1/2, NFκB p50, p300 and CBP signaling modules. Collectively, our results demonstrated that CIL-102 induced cell cycle arrest and apoptosis of colon cancer cells by upregulating p21 and GADD45 expression and by activating JNK1/2, NFκB p50 and p300 to provide a new mechanism for CIL-102 treatment., Competing Interests: The authors have declared that no competing interests exist.

A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative) and SW-48 (p53-positive) CRC cells and human umbilical vein endothelial cells (HUVECs) were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin.

The CC chemokine receptor 6 (CCR6) and its ligand CCL20 are involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. In addition, interleukin-17 (IL-17), produced by a T cell subset named "Th17," has been identified as an important player in inflammatory responses, and has emerged as a mediator in inflammation-associated cancer. However, the relevance of IL-17 in the development and progression of CRC still remains to be explored. This study aimed to investigate the effect of IL-17 on the cell migration of CRC cells. Human CRC HCT-116 cells were used to study the effect of IL-17 on CCR6 expression and cell migration in CRC cells. IL-17 treatment induced migration of HCT-116 cells across the Boyden chamber membrane and increased the expression level of the CCR6. Inhibition of CCR6 by small interfering RNA (siRNA) and neutralizing antibody inhibited IL-17-induced cell migration. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK and p38 pathways are critical for IL-17-induced CCR6 expression and cell migration. Promoter activity and transcription factor ELISA assays showed that IL-17 increased NF-κB-DNA binding activity in HCT-116 cells. Inhibition of NF-κB activation by specific inhibitors and siRNA blocked the IL-17-induced CCR6 expression. Our findings support the hypothesis that CCR6 up-regulation stimulated by IL-17 may play an active role in CRC cell migration., (© 2014 Wiley Periodicals, Inc.)

Obesity has been shown to be associated with the risk of colorectal cancer (CRC). Adipokines produced by the adipose tissue are linked to some malignancies, including CRC. Visfatin is an adipokine shown to be a biomarker of CRC malignant potential. In addition, the stromal cell-derived factor-1 (SDF-1) has been reported to play a role in CRC progression. Although the relationship between visfatin and CRC has been established, the underlying mechanism has not been clarified. We investigated the molecular mechanism governing the interaction between visfatin stimulation and SDF-1 expression in human CRC cell lines. We found that visfatin stimulation led to an increase in the expression and secretion of SDF-1 in CRC DLD-1 and SW48 cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of ERK and p38 mitogen-activated protein kinase (MAPK) pathways are critical for visfatin-induced SDF-1 expression. Analysis of transcription factor binding using ELISA and luciferase reporter assays revealed that visfatin increased NF-κB- and AP-1-DNA-binding activities in DLD-1 cells. Inhibition of NF-κB and AP-1 activation blocked the visfatin-induced expression and activity of the SDF-1 promoter. The effect of visfatin on DLD-1 signaling and SDF-1 expression was mediated by β1 integrin. In summary, these findings provide novel insights pertaining to the pathophysiological role of visfatin in CRC., (Copyright © 2012 Wiley Periodicals, Inc.)

The stromal cell-derived factor-1 (SDF-1)/CXC receptor 4 (CXCR4) axis has been shown to play a role in colorectal cancer progression. In addition, the protease urokinase-type plasminogen activator (uPA) is an important factor in tumor cell invasion and metastasis. However, the mechanism by which SDF-1 mediates uPA expression in human colorectal cancer cells remains unknown. We investigated the molecular mechanism governing the interaction between SDF-1 stimulation and uPA expression in three human colon cancer cell lines (DLD-1, SW48, and COLO 205). We found that SDF-1 stimulation led to an increase in the expression and secretion of uPA in these cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways are critical for SDF-1-induced uPA expression. Analysis of transcription factor binding using ELISA and chromatin immunoprecipitation assays revealed that SDF-1 increased Sp1- and AP-1-DNA-binding activities in DLD-1 cells. Inhibition of Sp1 and AP-1 activation blocked the SDF-1-induced expression and activity of the uPA promoter. The effect of SDF-1 on DLD-1 signaling and uPA expression was mediated by the CXCR4/β1 integrin axis. In summary, our findings elucidate the mechanisms of SDF-1/CXCR4 downstream signaling and provide insights into the function of SDF-1 in colon cancer cells., (Copyright © 2011 Wiley Periodicals, Inc.)

Baicalein is the flavonoids with multiple pharmacological activities. The aim of our study was to investigate the effects of baicalein on colorectal cancer (CRC) and to recognize the targets of baicalein treatment. To better understand baicalein's target, proteomic approaches were used to purify and identify the protein substrates using 2D difference gel electrophoresis (2D SDS-PAGE) to elucidate proteins differential display. Results from this study investigate that baicalein treatment of CRC cells results in reduced cell proliferation. As a result, differential protein displays between baicalein-treated and untreated CRC were determined and validated. There were 11 differentially expressed proteins between baicalein-treated and untreated CRC. Furthermore, we demonstrate that baicalein inhibits cancer cell proliferation and reduced reactive oxygen species (ROS) by up-regulating the levels of peroxiredoxin-6 (PRDX6). Knockdown of PRDX6 in baicalein-treated CRC cells by specific small interfering RNA resulted in ROS production and proliferation, opposite of the baicalein treatment scenario as indicated by cell cycle distribution. These results illustrate that baicalein up-regulates the expression of PRDX6, which attenuates the generation of ROS and inhibits the growth of CRC cells, whereas baicalein treatment have no effect on normal epithelial cells., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Although colonoscopy plays an important role in postoperative surveillance of patients with colorectal cancer, the optimum protocol for colonoscopic surveillance has not been established., Objective: Our purpose was to compare the efficacy of 2 different colonoscopic surveillance strategies in terms of both survival and recurrence resectability., Design: Prospective, randomized, controlled trial., Setting: A teaching hospital in Sun Yat-sen University., Patients: Three hundred twenty-six consecutive patients undergoing radical surgery for colorectal cancer., Intervention: In the intensive colonoscopic surveillance group (ICS group, n = 165), colonoscopy was performed at 3-month intervals for 1 year, at 6-month intervals for the next 2 years, and once a year thereafter. In the routine colonoscopic surveillance group (RCS group, n = 161), colonoscopy was performed at 6 months, 30 months, and 60 months postoperatively., Main Outcome Measurements and Results: The 5-year survival rate was 77% in the ICS group and 73% in the RCS group (P > .05). Postoperative colorectal cancer was detected in 13 patients (8.1%) in the ICS group and in 18 patients (11.4%) in the RCS group. In the ICS group, there were more asymptomatic postoperative colorectal cancers (P = .04), more patients had reoperation with curative intent (P = .048), and the probability of survival after postoperative colorectal cancer was higher (P = .03)., Limitation: Lack of detailed characterization of metachronous colorectal adenomas in these patients., Conclusions: Although the patients in the ICS group had more curative operations for postoperative colorectal cancer and survived significantly longer, ICS itself did not improve overall survival.

Purpose: Cyclin D1 is a regulatory protein involved in the cell cycle of both normal and neoplastic cells. Polymorphism of this gene at codon 242 in exon 4 has impacts on risk of the early-age onset in several malignant neoplasms, including colorectal cancer. This investigation was designed to evaluate the effect of cyclin D1 gene polymorphism on the risk of colorectal cancer in Chinese migrants of the Taiwanese population., Methods: We enrolled 831 primary sporadic colorectal cancer patients as the study group and 1,052 age-gender matched healthy individuals as the control group (1,883 total cases) for present study. Cyclin D1 genotypes (AA, AG, GG) were determined using PCR-RFLP analysis on genomic DNA., Results: The frequency of G allele was 39.89 percent and 40.96 percent in the study group and the control group, respectively (P = 0.02). The patients were divided into three age groups for statistical analysis. The younger male patients had a higher frequency of AA/AG genotype compared with the controls (odds ratio, 2.75; 95 percent confidence interval, 1-7.9). The effect of AA/AG genotype on colorectal cancer risk was statistically significant for male patients (odds ratio, 1.34; 95 percent confidence interval, 1.04-1.72), but such phenomenon was not observed in female patients., Conclusions: Our study suggests that the effect of cyclin D1 gene polymorphism on colorectal cancer risk is only observed in males and AA/AG genotype of cyclin D1 gene is associated with a higher risk of colorectal cancer in the younger patients within the Taiwanese population.