Scots pine (Pinus sylvestris L.) has higher early growth rates than Norway spruce (Picea abies (L.) H. Karst.). To help efforts to understand possible reasons for this difference and identify appropriate regeneration methods, we labeled seedlings with N-15 in the nursery to probe nitrogen (N) uptake and retranslocation in Scots pine and Norway spruce seedlings at both harsh and fertile sites in southern and northern Sweden. For this, N-15 dilution was measured during the first two years after planting. We also examined the potential N-2-fixation capacity in fine roots after 5-7 growing seasons. Use of N-15-labeled seedlings enabled clear discernment of contributions of uptake of new N and retranslocation of old N to new foliage. Scots pine seedlings had higher proportions of N derived from uptake (N-dfu) than Norway spruce seedlings, and higher growth. Scots pine seedlings were less responsive to site preparation treatments compared to Norway spruce that has a greater need for appropriate silvicultural measures to grow well. After the second growing season, the contribution of N derived from retranslocation (N-dfr) to N in new foliage had diminished to 10-20% at all except the harshest site, where both species were more dependent on N-dfr. The potential N-2-fixation capacity in fine roots of the two species differed, but in both cases the contribution of N-2-fixation to N-acquisition was negligible.

The tumor microenvironment (TME) is important in the recurrence and metastasis of colorectal cancer (CRC). Phillygenin is an effective component of Forsythiae fructus that has long been used in cancer therapy. The mechanism by which phillygenin regulates the TME remains unknown. Methods and Results: A co-culture system of CRC cells and Jurkat T cells was used to simulate the TME in vitro. Network pharmacology and Human XL cytokine arrays were used to preliminarily evaluate the role of phillygenin in the TME. The target of phillygenin was determined using transfection of plasmid-producing overexpression of hypoxia-inducible factor 1 alpha (HIF-1α) overexpression or abrogated HIF-1α expression via short hairpin RNA plasmid. The therapeutic effect of phillygenin in vivo was assessed in a subcutaneous tumor mouse model. In vitro, phillygenin enhanced the immune response of T cells and prevented the immune escape of cancer cells via the inhibition of HIF-1α. Phillygenin upregulated interleukin (IL)-2 and downregulates IL-10 and FOXP3 in Jurkat T cells co-cultured with CRC cells. Phillygenin inhibited expressions of HIF-1α, transforming growth factor-beta, vascular endothelial growth factor, and CD31 in CRC cells cultured alone or with Jurkat T cells. Phillygenin considerably suppressed tumor growth and improved the TME in vivo. Conclusions: Phillygenin can enhance the immune response and inhibit angiogenesis in the TME in CRC by inhibiting HIF-1α.

Colorectal cancer (CRC) continuously ranks as the third most common cause of cancer-related deaths worldwide. Based on anatomical classifications and clinical diagnoses, CRC is classified into right-sided, left-sided, and rectal CRC. Importantly, the three types of positional-specific CRC affect the prognosis outcomes, thus indicating that positional-specific treatments for CRC are required. Emerging evidence suggests that besides host genetic and epigenetic alterations, gut mucosal microbiota is linked to gut inflammation, CRC occurrence, and prognoses. However, gut mucosal microbiota associated with positional-specific CRC are poorly investigated. Here, we report the gut mucosal microbiota profiles associated with these three types of CRC. Our analysis showed that the unique composition and biodiversity of bacterial taxa are linked to positional-specific CRC. We found that a combination of bacterial taxa can serve as potential biomarkers to distinguish the three types of CRC. Further investigations of the physiological roles of bacteria associated with positional-specific CRC may help understand the mechanism of CRC progression in different anatomical locations under the impact of gut mucosal microbiota.

PURPOSETo evaluate the effectiveness of fecal immunochemical testing (FIT) in colorectal cancer screening.METHODSWe conducted a prospective cohort study among 5,598 participants age 40-74 years between 2012 and 2020 in Tianjin, China. Inverse probability weighting was adopted to adjust for potential imbalanced factors between groups. A Cox proportional hazards model was used to estimate the weighted associations between FIT screening and advanced colorectal neoplasia. A difference-in-difference (DID) model was adopted to compare the incidence rates of advanced colorectal neoplasia between groups.RESULTSIn DID analysis, the rate of incidence was reduced by 0.34 cases per person-years in the screening group as compared with the historical FIT screening group (rate ratio [RR], 0.08 [95% CI, 0.07 to 0.10]) and by 0.06 cases per person-years in the non-FIT screening group as compared with the historical non-FIT screening group (RR, 0.37 [95% CI, 0.29 to 0.48]; P < .001 for both comparisons), with a relative reduction of 0.28. Similar benefit effect from FIT screening was observed in sex and age subgroups.CONCLUSIONFIT screening was associated with a reduction in incidence density from advanced colorectal neoplasia.

AbstractBackgroundCurrent guidelines recommend colonoscopy‐based surveillance to decrease the risk of colorectal cancer (CRC) among these participants with above‐average risk. The fecal immunochemical test (FIT) holds promise as a viable alternative surveillance tool, but the existing evidence regarding the use of settings remains limited. Therefore, our aim is to evaluate the CRC incidence rates in individuals with above‐average CRC risk and the relationship between FIT surveillance and CRC incidence.MethodsThe retrospective cohort study was performed based on the CRC screening program between January 2012 and December 2022, in Tianjin, China. This cohort study included 12,515 participants aged 40–74 years with above‐average risk. The primary outcomes were the incidence rates of CRC and advanced colorectal neoplasia which were expressed as the number of events per 100,000 person‐years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.ResultsWe included 12,515 participants aged 40–74 years, of whom 4980 received subsequent FIT surveillance during the study period. Among these participants, 51 CRC cases occurred in the non‐FIT surveillance group (incidence rate, 233.88 per 100,000 person‐years) and there were 29 cases of CRC in the FIT surveillance group (incidence rate, 184.85 per 100,000 person‐years), resulting in an incidence rate ratio (IRR) of 0.58 (95% CI, 0.37–0.91). Meanwhile, 428 advanced colorectal neoplasia cases were reported in the non‐FIT surveillance group, while 269 cases occurred in the FIT surveillance group, with significantly lower incidence of advanced colorectal neoplasia in the FIT surveillance group (IRR: 0.64; 95% CI, 0.55–0.74). Compared with the non‐FIT surveillance group, the FIT surveillance group had a 54% decreased risk of developing CRC (HR, 0.46; 95% CI, 0.29–0.74) and a 45% decreased risk of developing advanced colorectal neoplasia (HR, 0.55; 95% CI, 0.47–0.64).ConclusionsIn this retrospective cohort study, above‐average risk individuals who received subsequent FIT in the intervals between colonoscopies were associated with a reduction of CRC and advanced colorectal neoplasia incidence, which indicated the value and utility of FIT in the surveillance program.

BackgroundOxaliplatin is the most common chemotherapeutic agent for patients with colorectal cancer. However, its anti-cancer efficacy is restricted by drug resistance occurring through several mechanisms, including autophagy. Liensinine exerts a considerable anti-tumor effect and can regulate autophagy. Inhibition of autophagy is a strategy to reverse resistance to oxaliplatin. The aim of this study was to check if liensinine can enhance the therapeutic efficacy of oxaliplatin in colorectal cancer and if so, elucidate its mechanism.MethodsTwo colorectal cancer cell lines, HCT116 and LoVo, and one normal intestinal epithelial cell, NCM-460 were used for in vitro experiments. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the cytotoxicity of liensinine and oxaliplatin. Network pharmacology analysis and Human XL Oncology Array were used to screen targets of liensinine. Transfections and autophagy regulators were used to confirm these targets. The relationship between the target and clinical effect of oxaliplatin was analyzed. Patient-derived xenograft (PDX) models were used to validate the effects of liensinine and oxaliplatin.ResultsCCK-8 and colony formation assays both showed that the combination treatment of liensinine and oxaliplatin exerted synergistic effects. Results of the network pharmacology analysis and Human XL Oncology Array suggested that liensinine can inhibit autophagy by targeting HIF-1α/eNOS. HIF-1α was identified as the key factor modulated by liensinine in autophagy and induces resistance to oxaliplatin. HIF-1α levels in tumor cells and prognosis for FOLFOX were negatively correlated in clinical data. The results from three PDX models with different HIF-1α levels showed their association with intrinsic and acquired resistance to oxaliplatin in these models, which could be reversed by liensinine.ConclusionsResearch on the relationship between HIF-1α levels and the clinical effect of oxaliplatin is lacking, and whether liensinine regulates HIF-1α is unknown. Our findings suggest that liensinine overcomes the resistance of colorectal cancer cells to oxaliplatin by suppressing HIF-1α levels to inhibit autophagy. Our findings can contribute to improving prognosis following colorectal cancer therapy.

Phenolic-laden wastewater is typically characterized by its high toxicity and high salinity, imposing serious limits on the application of bioremediation. Although a few halotolerant microorganisms have been reported to degrade phenol, their removal efficiency on high concentrations of phenol remains unsatisfactory. What's more, the deep interaction molecular mechanism of salt-tolerance/phenol-degradation performance has not been clearly revealed. Here, a halotolerant strain Aeribacillus pallidus W-12 employed a meta-pathway to efficiently degrade high concentration of phenol even under high salinity conditions. Investigation of salt-tolerance strategy indicated that four Na+/H+ antiporters, which are widely distributed in bacteria, synergistically endowed the strain with excellent salt adaptability. All these antiporters differentially but positively responded to salinity changes and induction of phenol, forming a synergistic transport effect on salt ions and phenol. In-depth analysis revealed a competitive relationship between salt tolerance and degradation performance, which significantly impaired the degradation efficiency at relatively high salinity. The efficient degradation performance of W-12 under different phenol concentrations and salinity conditions indicated its bioremediation potential for multiple types of phenolic wastewater. Collectively, the competitive mechanism of salt tolerance and degradation performance enlightens a new strategy of introducing or re-constructing Na+/H+ antiporters to further improve bioremediation efficiency of hypersaline organic wastewater.

Background:Prior studies have affirmed the safety and effectiveness of traditional Chinese medicine in treating colorectal cancer patients.However,definitive evidence regarding whether traditional Chinese medicine can significantly enhance the survival of colorectal cancer patients remains elusive.This study seeks to provide conclusive insights by examining the postoperative administration of Xihuang capsules,Pingxiao capsules,and Zilongjin tablets and its impact on the 5-year overall survival(OS)and disease-free survival(DFS)rates among colorectal cancer patients. Methods:A retrospective study was conducted,involving 1,361 patients selected from the medical center.This retrospective study was carried out at a medical center in Tianjin,China.We assessed differences in postoperative OS and DFS between the control group and the medication group using Kaplan-Meier survival analysis and Cox proportional hazards modeling.Additionally,propensity score matching was used to mitigate imbalances in baseline characteristics among patients. Results:Before propensity score matching,Xihuang capsules could prolong the 5-year OS(79.9％vs.81.4％,P=0.0480)and 5-year DFS(74.9％vs.79.5％,P=0.0046)of patients after surgery.Similar conclusions were obtained after propensity score matching:OS(74.8％vs.78.3％,P=0.0084),DFS(72.7％vs.78.9％,P=0.008).Patients taking Pingxiao capsules showed improved 5-year OS(77.2％vs.84.0％,P=0.0383)and 5-year DFS(69.9％vs.80.0％,P=0.0157)after propensity score matching.Patients taking Zilongjin tablets showed improvement in the 2-year OS(84.2％vs.93.1％,P=0.0390)and 1-year DFS(88.2％vs.92.0％,P=0.0320)after propensity score matching. Conclusion:Xihuang capsules and Pingxiao capsules significantly improved the 5-year OS and DFS of patients with colorectal cancer after surgery.Zilongjin tablets showed improvement in the 2-year OS and 1-year DFS after surgery for patients.

BACKGROUND:Cetuximab, an inhibitor targeting EGFR, is widely applied in clinical management of colorectal cancer (CRC). Nevertheless, drug resistance induced by KRAS-mutations limits cetuximab's anti-cancer effectiveness. Furthermore, the persistent activation of EGFR-independent AKT is another significant factor in cetuximab resistance. Nevertheless, the mechanism that EGFR-independent AKT drives cetuximab resistance remains unclear. Thus, highlighting the need to optimize therapies to overcome cetuximab resistance and also to explore the underlying mechanism.PURPOSE:This work aimed to investigate whether and how andrographolide enhance the therapeutic efficacy of cetuximab in KRAS-mutant CRC cells by modulating AKT.METHODS:The viabilities of CRC cell lines were analyzed by CCK-8. The intracellular proteins phosphorylation levels were investigated by Human Phospho-kinase Antibody Array analysis. Knockdown and transfection of PDGFRβ were used to evaluate the role of andrographolide on PDGFRβ. The western blotting was used to investigate Wnt/β-catenin pathways, PI3K/AKT, and EMT in KRAS-mutant CRC cells. The animal models including subcutaneous tumor and lung metastasis were performed to assess tumor response to therapy in vivo.RESULTS:Andrographolide was demonstrated to decrease the expression of PI3K and AKT through targeting PDGFRβ and EGFR, and it enhanced cetuximab effect on KRAS-mutant CRC cells by this mechanism. Meanwhile, andrographolide helped cetuximab to inhibit Wnt/β-catenin, CRC cell migration and reduced Vimentin expression, while increasing that of E-cadherin. Lastly, co-treatment with cetuximab and andrographolide reduced the growth of KRAS-mutant tumors and pulmonary metastases in vivo.CONCLUSIONS:Our findings suggest that andrographolide can overcome the KRAS-mutant CRC cells' resistance to cetuximab through inhibiting the EGFR/PI3K/AKT and PDGFRβ /AKT signaling pathways. This research provided a possible theory that andrographolide sensitizes KRAS-mutant tumor to EGFR TKI.

Introduction:Tumor-infiltrating T lymphocytes in the tumor microenvironment are critical factors influencing the prognosis and chemotherapy outcomes. As a Chinese herbal medicine, Marsdenia tenacissima extract (MTE) has been widely used to treat cancer in China. Its immunoregulatory effects on tumor-associated macrophages is well known, but whether it regulates tumor-infiltrating T-cell functions remains unclear.Method:We collected 17 tumor samples from MTE-administered colorectal cancer patients, 13 of which showed upregulation of CD3+/CD8+ tumor-infiltrating T cells. Further in vitro and in vivo experiments were performed to investigate the regulatory effects of MTE on tumor-infiltrating T cells and immune escape of tumors.Results:Under single and co-culture conditions, MTE inhibited TGF-β1 and PD-L1 expression in the colorectal cancer (CRC) cell lines HCT116 and LoVo. In Jurkat cells, MTE inhibited FOXP3 and IL-10 expression, increased IL-2 expression, but had no effect on PD-1 expression. These findings were confirmed in vitro using subcutaneous and colitis-associated CRC mouse models. MTE also increased the density of CD3+/CD8+ tumor-infiltrating T cells and exhibited considerable tumor-suppressive effects in these two tumor mouse models.Conclusions:Our findings suggested that MTE inhibits the immune escape of cancer cells, a precipitating factor increasing the immune response of T lymphocytes.

Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is extensively used for clinical therapy in KRAS wild-type colorectal cancer (CRC) patients. However, some patients still cannot get benefit from the therapy, because metastasis and resistance occur frequently after cetuximab treatment. New adjunctive therapy is urgently needed to suppress metastasis of cetuximab-treated CRC cells. In this study, we used two KRAS wild-type CRC cells, HT29 and CaCo2, to investigate whether platycodin D, a triterpenoid saponin isolated from Chinese medicinal herb Platycodon grandifloras, is able to suppress the metastasis of cetuximab-treated CRC. Label-free quantitative proteomics analyses showed that platycodin D but not cetuximab significantly inhibited expression of β-catenin in both CRC cells, and suggested that platycodin D counteracted the inhibition effect of cetuximab on cell adherence and functioned in repressing cell migration and invasion. Western blot results showed that single platycodin D treatment or combined platycodin D and cetuximab enhanced inhibition effects on expressions of key genes in Wnt/β-catenin signaling pathway, including β-catenin, c-Myc, Cyclin D1 and MMP-7, compared to single cetuximab treatment. Scratch wound-healing and transwell assays showed that platycodin D combined with cetuximab suppressed migration and invasion of CRC cells, respectively. Pulmonary metastasis model of HT29 and CaCo2 in nu/nu nude mice consistently showed that combined treatment using platycodin D and cetuximab inhibited metastasis significantly in vivo. Our findings provide a potential strategy to inhibit CRC metastasis during cetuximab therapy by addition of platycodin D.

BACKGROUND:Emerging evidence links gut microbiota to various human diseases including colorectal cancer (CRC) initiation and development. However, gut microbiota profiles associated with CRC recurrence and patient prognosis are not completely understood yet, especially in a Chinese cohort. AIM:To investigate the relationship between gut mucosal microbiota profiles and CRC recurrence and patient prognosis. METHODS:We obtained the composition and structure of gut microbiota collected from 75 patients diagnosed with CRC and 26 healthy controls. The patients were followed up by regular examination to determine whether tumors recurred. Triplet-paired samples from on-tumor, adjacent-tumor and off-tumor sites of patients diagnosed with/without CRC recurrence were analyzed to assess spatial-specific patterns of gut mucosal microbiota by 16S ribosomal RNA sequencing. Next, we carried out bioinformatic analyses, Kaplan-Meier survival analyses and Cox regression analyses to determine the relationship between gut mucosal microbiota profiles and CRC recurrence and patient prognosis. RESULTS:We observed spatial-specific patterns of gut mucosal microbiota profiles linked to CRC recurrence and patient prognosis. A total of 17 bacterial genera/families were identified as potential biomarkers for CRC recurrence and patient prognosis, including Anaerotruncus, Bacteroidales, Coriobacteriaceae, Dialister, Eubacterium, Fusobacterium, Filifactor, Gemella, Haemophilus, Mogibacteriazeae, Pyramidobacter, Parvimonas, Porphyromonadaceae, Slackia, Schwartzia, TG5 and Treponema. CONCLUSION:Our work suggests that intestinal microbiota can serve as biomarkers to predict the risk of CRC recurrence and patient death.

BACKGROUND Patients with recurrent or locally advanced head and neck squamous cell carcinoma (HNSCC) typically have limited treatment options and poor prognosis. AIM To evaluate the efficacy and safety of two drugs with potent radio-sensitization properties including gemcitabine and nedaplatin as concurrent chemoradiotherapy regimens in treating HNSCC. METHODS This single-arm prospective study enrolled patients with HNSCC to receive gemcitabine on days 1 and 8 and nedaplatin on days 1 to 3 for 21 days. Intensity-modulated radiation therapy with a conventional fraction was delivered 5 days per week. Objective response rate (ORR), disease control rate, and toxicity were observed as primary endpoints. Overall survival (OS) and progression free survival were recorded and analyzed as secondary endpoints. RESULTS A total of 24 patients with HNSCC were enrolled. During the median 22.4-mo follow-up, both ORR and disease control rate were 100%. The one-year OS was 75%, and one-year progression-free survival (PFS) was 66.7% (median PFS was 15.1 mo). Recurrent HNSCC patients had a poorer prognosis than the treatment-naïve patients, and patients who achieved complete response had better survival than those in the PR group (all P < 0.05). The most common grade 1-4 (100%) or grade 3-4 toxicities (75%) were hematological, and the most common grade 3-4 non-hematological toxicity was mucositis in 17 (71%) patients. CONCLUSION Gemcitabine plus nedaplatin with concurrent chemoradiotherapy is a therapeutic option for HNSCC with predictable tolerability. Considering the high adverse event rate, the optimized dose and schedule must be further explored.

Cetuximab is a monoclonal antibody against epidermal growth factor receptor that blocks downstream signaling pathways of receptor tyrosine kinases, including Ras/Raf/MAPK and PI3K/Akt, thereby inhibiting tumor cell proliferation and inducing cancer cell apoptosis. Owing to KRAS mutations, the effectiveness of cetuximab is usually limited by intrinsic drug resistance. Continuous activation of the PI3K/Akt signaling pathway is another reason for cetuximab resistance. Platycodin-D, a bioactive compound isolated from the Chinese herb Platycodon grandiflorum, regulates Akt in different trends based on tissue types. To investigate whether platycodin-D can sensitize KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway, HCT116 and LoVo cells were treated with cetuximab and platycodin-D. LY294002 and SC79 were used to regulate Akt to further evaluate whether platycodin-D sensitizes cells to cetuximab by inhibiting Akt. Our results confirmed that platycodin-D increased the cytotoxic effects of cetuximab, including inhibition of growth, migration, and invasion, via downregulation of PI3K and Akt phosphorylation in HCT116 and LoVo cells both in vitro and in vivo. Given these data, platycodin-D may sensitize KRAS-mutant colorectal cancer cells to cetuximab via inhibition of the PI3K/Akt signaling pathway.

BACKGROUND:Photodynamic therapy could be one approach to treat colorectal cancer though resistance leads to failure of therapy. Akt activation is a cellular survival response to photodynamic therapy and is also a reason for resistance. Thus, inhibition of Akt is a strategy to decrease resistance. Akt interacts with connexin 43, another protein involved in photodynamic therapy resistance. Connexin 43 is widely expressed in different human tissues and has a complex role in tumor development. However, the mechanism of inhibition of Akt by connexin 43 that sensitizes colorectal cancer cells to photodynamic therapy needs further investigation.METHODS:In this study, two colorectal cancer cells with low phosphorylated connexin 43 level were used to explore this mechanism. LY294002 was used as an Akt inhibitor, and connexin 43-pCMV3 was transfected into cells to increase connexin 43 expression.RESULTS:Akt and connexin 43 inhibit each other in both colorectal cancer cell lines. In vitro and in vivo experiments showed that LY294002 and connexin 43 transfection sensitized cells to hematoporphyrin-Photodynamic therapy. LY294002 increased the sensitivity of cells to photodynamic therapy with a pronounced effect in cells with high expression levels of connexin 43.CONCLUSIONS:Connexin 43 should be considered an important factor in increasing the phototoxicity of photodynamic therapy in colorectal cancer through Akt inhibition.

Emerging evidences link gut microbiota to colorectal cancer (CRC) initiation and development. However, the CRC stage- and spatial-specific bacterial taxa were less investigated, especially in a Chinese cohort, leading to our incomplete understanding of the functional roles of gut microbiota in promoting CRC progression and recurrence. Here, we report the composition and structure of gut microbiota across CRC stages I, II and III, by analyzing the gut mucosal microbiomes of 75 triplet-paired samples collected from on-tumor, adjacent-tumor and off-tumor sites and 26 healthy controls. We observed tumor-specific pattern of mucosal microbiome profiles as CRC progressed and identified ten bacterial taxa with high abundances (>1%) as potential biomarkers for tumor initiation and development. Peptostreptococcus and Parvimonas can serve as biomarkers for CRC stage I. Fusobacterium, Streptococcus, Parvimonas, Burkholderiales, Caulobacteraceae, Delftia and Oxalobacteraceae can serve as biomarkers for CRC stage II, while Fusobacterium, Burkholderiales, Caulobacteraceae, Oxalobacteraceae, Faecalibacterium and Sutterella can serve as biomarkers for CRC stage III. These biomarkers classified CRC stages I, II and III distinguished from each other with an area under the receiver-operating curve (AUC) > 0.5. Moreover, co-occurrence and co-excluding network analysis of these genera showed strong correlations in CRC stage I, which were subsequently reduced in CRC stages II and III. Our findings provide a reference index for stage-specific CRC diagnosis and suggest stage-specific roles of Peptostreptococcus, Fusobacterium, Streptococcus and Parvimonas in driving CRC progression.

Background Inflammatory bowel disease caused by microbial dysbiosis is an important factor contributing to colorectal cancer (CRC) initiation. The ‘driver-passenger’ model in human gut microbial dysbiosis suggests that ‘driver’ bacteria may colonize with low relative abundance on tumor site but persistently induce chronic change in normal intestinal epithelium and initiate CRC. They are gradually replaced by ‘passenger’ bacteria later on, due to their low adaptability to the on-tumor site niche. Results To reveal site-specific bacterial taxon markers in CRC patients, we analyzed the gut mucosal microbiome of 75 paired samples of on-tumor and tumor-adjacent sites, 75 off-tumor sites, and 26 healthy controls. Linear discriminant analysis of relative abundance profiles revealed unique bacterial taxon distribution correlated with specific tumor sites, with Eubacterium having the distribution characteristic of potential driver bacteria. We further show that Eubacterium rectale endotoxin activates the transcription factor NF-κΒ, which regulates multiple aspects of innate and adaptive immune responses in normal colon epithelial cells. Unlike the ‘passenger’ bacterium Fusobacterium nucleatum , E. rectale promotes dextran sodium sulfate-induced colitis in Balb/c mice. Conclusions Our findings reveal that E. rectale functions as a ‘driver’ bacterium and contributes to cancer initiation via promoting inflammation.

Cetuximab is a monoclonal antibody that acts as an anti-epidermal growth factor receptor (EGFR) agent. Cetuximab inhibits the phosphorylation and activation of EGFR and blocks downstream signal pathways of EGF/EGFR, including Ras-Raf-MAPK and PI3K-Akt pathways. Akt activation is an important factor in cetuximab resistance. It has been reported that resveratrol and connexin 43 regulate Akt in different ways based on tissue type. Since connexin 43 interacts with Akt, and resveratrol is known to upregulate connexin 43, we investigated whether resveratrol can sensitize colorectal cancer cells to cetuximab via connexin 43 upregulation. Our work confirmed that resveratrol increases the inhibition of growth by cetuximab in vitro and in vivo, upregulates connexin 43 expression and phosphorylation, increases gap junction function, and inhibits the activation of Akt and NFκB in parental or cetuximab-treated parental HCT116 and CT26 cells. Resveratrol did not exhibit these effects on connexin 43-shRNA transfected cells, so connexin 43 upregulation may contribute to Akt inhibition in these cells. Given these data, resveratrol may sensitize colorectal cancer cells to cetuximab via upregulating connexin 43 to inhibit the Akt pathway.

1Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, People’s Republic of China; 2Department of Colorectal Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, People’s Republic of China; 3Advanced Studies in Genomics, Proteomics, and Bioinformatics, University of Hawaii at Manoa, Honolulu, HI, USA; 4Department of Radiology, Tianjin Union Medical Center, Nankai University, Tianjin, People’s Republic of China; 5TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, People’s Republic of China