The Type-B Cytokinin Response Regulator ARR1 Inhibits Shoot Regeneration in an ARR12-Dependent Manner in Arabidopsis.

Exogenous cytokinin is critical for in vitro shoot regeneration. Proteins involved in the cytokinin signal transduction pathway, including type-B ARABIDOPSIS RESPONSE REGULATORs (ARRs), participate in shoot regeneration in Arabidopsis (Arabidopsis thaliana). Some type-B ARRs (e.g., ARR1 and ARR12) promote shoot regeneration by directly activating WUSCHEL (WUS) expression; however, it is unclear how type-B ARRs inhibit shoot regeneration. Here, we show that ARR12 is a central enhancer of callus formation and shoot regeneration, whereas ARR1 is a strong inhibitor of this process that counteracts the positive effect of ARR12. ARR1 indirectly represses CLAVATA3 (CLV3) expression in an ARR12-dependent manner via competing with ARR12 for binding to the CLV3 promoter, which contributes to its ARR12-dependent inhibitory effect on callus formation and shoot regeneration. In parallel, ARR1 inhibits shoot regeneration through transcriptional activation of INDOLE-3-ACETIC ACID INDUCIBLE17, an auxin response repressor gene, and the consequent indirect repression of WUS expression. Thus, type-B ARRs have diverse effects on callus formation and shoot regeneration. Our study reveals novel molecular pathways linking cytokinin signaling, the CLV3 regulator, and auxin signaling, and sheds light on the mechanism underlying cytokinin-regulated shoot regeneration.

Posttranscriptional control of intestinal epithelium homeostasis by RNA-binding protein HuR.

The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body and directly interfaces with a wide array of luminal noxious contents and microorganisms. Homeostasis of the intestinal epithelium is preserved through well-controlled mechanisms including posttranscriptional regulation. RNA-binding protein (RBP) HuR regulates the stability and translation of target mRNAs and is intimately involved in many aspects of gut mucosal pathophysiology. Here we highlight the biological roles of HuR in maintaining the integrity of the intestinal epithelium, with particular focus on the emerging evidence of HuR in the regulation of intestinal epithelial renewal, mucosal repair, defense, and gut permeability. We also further analyze the mechanisms through which HuR and its interactions with other RBPs and noncoding RNAs (ncRNAs) such as microRNAs and long ncRNAs modulate the intestinal epithelial homeostasis. With rapidly advancing knowledge of RBPs and ncRNAs, there is growing recognition that posttranscriptional control of the intestinal epithelium homeostasis might be promising therapeutic targets in our efforts to protect the integrity of the intestinal epithelium under critical pathological conditions.

Aberrant accumulation of Kras-dependent pervasive transcripts during tumor progression renders cancer cells dependent on PAF1 expression.

KRAS is the most commonly mutated oncogene in human cancer, and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II-associated factor 1 complex (PAF1C) is specifically required for survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining overaccumulation of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of pervasive transcripts on chromatin and concomitant aberrant R-loop formation and DNA damage, which, in turn, trigger cell death. We go on to demonstrate that the global transcriptional hyperactivation driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides insights into how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.

Application of Vagus Nerve Branch Preservation in Thoracoscopic Surgery for Early-Stage Lung Cancer.

Background: In this study, we introduced a novel surgical strategy to protect vagal nerve branches during radical thoracoscopic surgery in right lung cancer and explored the effects of vagal nerve branch preservation. Methods: We retrospectively studied 53 patients with right-sided lung cancer with clinically staged T1N0M0 between 2019 and 2020. All 53 patients were treated with total thoracoscopic lobectomy and mediastinal lymph node dissection in the same number of lymph node stations. Of these, 22 patients adopted a vagus nerve branch protection strategy during lymph node dissection. Another 31 patients were treated with traditional lymph node dissection as the control group. Results: The characteristics of the patients were similar between the two groups. The operation time and intraoperative bleeding in the protection group were longer than those in the control group. However, the protection group had a lower average postoperative pain score and average postoperative hospital stay. The above difference was not statistically significant. Three cases of arrhythmia occurred in the protection group, including 1 case of tachycardia and 2 cases of atrial fibrillation. In the control group, 13 cases of arrhythmia occurred after the operation, including 8 cases of tachycardia and 5 cases of atrial fibrillation. We also tracked changes in the patients' heart rates throughout the treatment process (excluding patients with arrhythmias). An increased heart rate was observed postoperatively in both groups, but the increase of heart rate of the protection group was smaller than that of the control group; however, the difference was not statistically significant. Conclusions: A vagus nerve branch preservation-based approach to radical surgery is a safe and feasible strategy for right lung cancer treatment, which could significantly reduce the risk of postoperative arrhythmia in patients and may also have a potential role in reducing the length of hospital stay and maintaining heart rate stability in the postoperative period.

Clinicopathological significance of DAPK gene promoter hypermethylation in non-small cell lung cancer: A meta-analysis.

BACKGROUND: Death-associated protein kinase (DAPK) has a strong function of tumor suppression involving apoptosis regulation, autophagy, and metastasis inhibition. Hypermethylation of CpG islands in DAPK gene promoter region is one of the important ways to inactivate this tumor suppressor gene, which might promote lung carcinogenesis. However, the clinicopathological significance of the DAPK promoter hypermethylation in lung cancer remains unclear. In this study, we performed a meta-analysis trying to estimate the clinicopathological significance of DAPK promoter hypermethylation in non-small cell lung cancer (NSCLC). METHODS: A detailed literature search for publications relevant to DAPK gene promoter methylation and NSCLC was made in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, CSTJ, Wanfang databases, and SinoMed (CBM). The random-effects model and fixed-effects model were utilized to pool the relative ratio based on the heterogeneity test in the meta-analysis. RESULTS: A total of 41 studies with 3348 patients were included. The frequency of DAPK methylation was significantly higher in NSCLC than in non-malignant control (odds ratio (OR) = 6.88, 95% confidence interval (CI): 4.17-11.35, P < 0.00001). The pooled results also showed that DAPK gene promoter hypermethylation was significantly associated with poor prognosis for overall survival in patients with NSCLC (hazard ratio: 1.23, 95% CI:1.01-1.52, P = 0.04). Moreover, DAPK gene promoter hypermethylation was significantly associated with squamous cell carcinoma (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04) and smoking behavior (OR: 1.42, 95% CI: 1.04-1.93, P = 0.03) but not with TNM stage, tumor differentiation, age, or gender. CONCLUSION: DAPK promoter hypermethylation might be a candidate diagnostic and prognostic tumor marker for NSCLC.

Signatures associated with homologous recombination deficiency and immune regulation to improve clinical outcomes in patients with lung adenocarcinoma.

PARP inhibitors can be used to treat solid tumors that often have mutations in important homologous recombination (HR) genes, such as BRCA1/2. While other kinds of tumors could also experience HR deficiencies, including those associated with lung cancer, there is little information on the frequency of these occurrences. Homologous recombination deficiency (HRD) was used to induce particular DNA aberration profiles and related transcriptome alterations. Their presence can identify whether an HR deficiency is present or absent in a particular tumor sample, even without observed HR gene changes. From whole-exome sequencing data in lung adenocarcinoma obtained from TCGA, we obtained several mutational signatures associated with HRD and determined that these HRD-associated mutational signatures are related to genomic installability. We then constructed a prediction model, which found that 11 genes associated with HRD scores could be used as predictors of survival outcomes in LUAD patients. These genes are related to PI3K-Akt, T cell receptors, and the Chemokine pathway. Other GEO datasets validated the survival prediction, which was independent of the PD1/PDL1 treatment. Collectively, our study provides transcriptome biomarkers of lung adenocarcinoma complementary to the HRD score and introduces a novel method of identifying prognostic biomarkers of immunotherapy.

Long noncoding RNA uc.230/CUG-binding protein 1 axis sustains intestinal epithelial homeostasis and response to tissue injury.

Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.

[Clinical significance of radical cystectomy with extended lymphadenectomy].

OBJECTIVE: To evaluate the prognosis of patients treated with radical cystectomy and extended lymphadenectomy for invasive bladder cancer and to describe the association of the primary bladder tumor grade, stage, lymph node status and lymph node density with clinical outcomes. METHODS: A retrospective analysis was done of 32 consecutive cases with bladder cancer who received radical cystectomy and extended lymph node dissection from January 2006 to December 2010 in the Department of Urology, Peking University First Hospital. All the patients were scheduled for the follow-up. The survival data were analyzed with the tumor grade, stage, lymph node status and other factors that might relate to the prognosis by statistics. RESULTS: All the cases were diagnosed as invasive urothelial bladder cancer by preoperative biopsy or TUR-Bt. During the follow-up, 6 patients (18.8%) got disease progression, and 4 patients died (12.5%). Overall survival rate was 87.5%. In 32 patients, 17 months and 3 year survival rates were (88.7 ± 12.1)% and (81.8 ± 17.0)%, respectively. From the tumor grade point of view, 6 patients belonged to G2, and 26 cases G3. All deaths were graded G3. G3-class 3-year survival rate was (74.6 ± 23.9)% (P> 0.05, compared with G2). From the analysis of stage, T1 and T2 stages had no death during the follow-up. The 17-month survival rate of T3 group was (60.0 ± 42.9)%, the 8-month survival rate of T4 group was (87.5 ± 22.9)%. There were 9 patients with positive lymph nodes (28.1%) and 23 with negative in (71.9%). The number of dissection lymph nodes was from 7-50 ( average 22.8 ). The 17-month survival rate of patients with positive lymph node was (50.0 ± 44.6)%. The 3-year survival rate of patients with negative lymph node was (92.3 ± 14.5)% (P<0.05). The 3-year survival rate of patients with lymph node density less than 20% was (88.8 ± 15.4)%. The 8-month survival rate of patients with lymph node density greater than 20% was (66.7 ± 53.3)% (P<0.05). CONCLUSION: Radical cystectomy with extended lymph node dissection can improve the prognosis of patients with invasive bladder cancer. Tumor stage, lymph node status and lymph node density are closely related to the patient's survival.

The Prognosis and Immune Checkpoint Blockade Efficacy Prediction of Tumor-Infiltrating Immune Cells in Lung Cancer.

BACKGROUNDS: The high morbidity and mortality of lung cancer are serious public health problems. The prognosis of lung cancer and whether to apply immune checkpoint blockade (ICB) are currently urgent problems to be solved. METHODS: Using R software, we performed Kaplan-Meier (K-M) analysis, Cox regression analysis, functional enrichment analysis, Spearman correlation analysis, and the single-sample gene set enrichment analysis. RESULTS: On the Tumor IMmune Estimation Resource (TIMER2.0) website, we calculated the abundance of tumor-infiltrating immune cells (TIICs) of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. B cell and myeloid dendritic cell (DC1) were independent prognostic factors for LUAD and LUSC patients, respectively. Enrichment analysis confirmed that genes highly related to B cell or DC1 were closely related to the immune activation of lung cancer patients. In terms of adaptive immune resistance markers, CD8A, CD8B, immunomodulators (immunostimulants, major histocompatibility complex, receptors, and chemokines), immune-related pathways, tumor microenvironment score, and TIICs, high B cell/DC1 infiltration tissue was inflamed and immune-activated and might benefit more from the ICB. Genes most related to B cell [CD19, toll-like receptor 10 (TLR10), and Fc receptor-like A (FCRLA)] and DC1 (ITGB2, LAPTM5, and SLC7A7) partially clarified the roles of B cell/DC1 in predicting ICB efficacy. Among the 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, there were three and four KEGG pathways, which partially explained the molecular mechanisms by which B cell and DC1 simultaneously predicted the prognosis and efficacy of immunotherapy, respectively. Among five immune subtypes, the abundance of B cell/DC1 and expression of six hub genes were higher in immune C2, C3, and C6. CONCLUSION: B cell and DC1 could predict the prognosis and ICB efficacy of LUAD and LUSC patients, respectively. The six hub genes and seven KEGG pathways might be novel immunotherapy targets. Immune C2, C3, and C6 subtypes of lung cancer patients might benefit more from ICB therapy.

The diagnostic value of the combination of carcinoembryonic antigen, squamous cell carcinoma-related antigen, CYFRA 21-1, neuron-specific enolase, tissue polypeptide antigen, and progastrin-releasing peptide in small cell lung cancer discrimination.

BACKGROUND: The diagnostic value of six tumor markers was investigated and the appropriate combinations of those tumor markers to discriminate small cell lung cancer was explored. METHODS: Patients suspected with lung cancer (1938) were retrospectively analyzed. Candidate tumor markers from carcinoembryonic antigen (CEA), squamous cell carcinoma-related antigen (SCC), cytokeratin 19 fragment 21-1 (CYFRA 21-1), neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), and progastrin releasing peptide (ProGRP) were selected to construct a logistic regression model. The receiver operating characteristic curve was used for evaluating the diagnostic value of the tumor markers and the predictive model. RESULTS: ProGRP had the highest positive rate (72.3%) in diagnosed small cell lung cancer, followed by neuron-specific enolase (68.3%), CYFRA21-1 (50.5%), carcinoembryonic antigen (45.5%), tissue polypeptide antigen (30.7%), and squamous cell carcinoma-related antigen (5.9%). The predictive model for small cell lung cancer discrimination was established, which yielded the highest area under the curve (0.888; 95% confidence interval: 0.846-0.929), with a sensitivity of 71.3%, a specificity of 95.0%, a positive predictive value of 49.0%, and a negative predictive value of 98.0%. CONCLUSIONS: Combining tumor markers can improve the efficacy for small cell lung cancer discrimination. A predictive model has been established in small cell lung cancer differential diagnosis with preferable efficacy.

BCL2A1 and CCL18 Are Predictive Biomarkers of Cisplatin Chemotherapy and Immunotherapy in Colon Cancer Patients.

Background: Cisplatin enhances the antitumor T cell response, and the combination of PD-L1 blockade produces a synergistic therapeutic effect. However, the clinical correlation between cisplatin and immunotherapy in colon cancer (CC) is unknown. Methods: Using the "pRRophetic" package, we calculated the IC50 of cisplatin. The correlation between cisplatin IC50, cisplatin resistance-related genes (CCL18 and BCL2A1), and immunotherapy were preliminarily verified in TCGA and further validated in independent cohorts (GSE39582 and GSE17538), cisplatin-resistant CC cell line DLD1, and our own clinical specimens. Classification performance was evaluated using the AUC value of the ROC curve. Scores of immune signatures, autophagy, ferroptosis, and stemness were quantified using the ssGSEA algorithm. Results: Based on respective medians of three CC cohorts, patients were divided into high- and low-IC50 groups. Compared with the high IC50 group, the low-IC50 group had significantly higher tumor microenvironment (TME) scores and lower tumor purity. Most co-signaling molecules were upregulated in low IC50 group. CC patients with good immunotherapy efficacy (MSI, dMMR, and more TMB) were more attributable to the low-IC50 group. Among seven shared differentially expressed cisplatin resistance-related genes, CCL18 and BCL2A1 had the best predictive efficacy of the above immunotherapy biomarkers. For wet experimental verification, compared with cisplatin-resistant DLD1, similar to PD-L1, CCL18 and BCL2A1 were significantly upregulated in wild-type DLD1. In our own CC tissues, the mRNA expression of CCL18, BCL2A1, and PD-L1 in dMMR were significantly increased. The high group of CCL18 or BCL2A1 had a higher proportion of MSI, dMMR, and more TMB. IC50, CCL18, BCL2A1, and PD-L1 were closely related to scores of immune-related pathways, immune signatures, autophagy, ferroptosis, and stemness. The microRNA shared by BCL2A1 and PD-L1, hsa-miR-137, were significantly associated with CCL18, BCL2A1, and PD-L1, and downregulated in low-IC50 group. The activity of the TOLL-like receptor signaling pathway affected the sensitivity of CC patients to cisplatin and immunotherapy. For subtype analysis, immune C2, immune C6, HM-indel, HM-SNV, C18, and C20 were equally sensitive to cisplatin chemotherapy and immunotherapy. Conclusions: CC patients sensitive to cisplatin chemotherapy were also sensitive to immunotherapy. CCL18 and BCL2A1 were novel biomarkers for cisplatin and immunotherapy.

Interaction between HuR and circPABPN1 Modulates Autophagy in the Intestinal Epithelium by Altering ATG16L1 Translation.

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens, and defects in this process occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy-related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa. Intestinal mucosa from patients with IBD exhibited reduced levels of both HuR and ATG16L1. HuR directly interacted with Atg16l1 mRNA via its 3' untranslated region and enhanced ATG16L1 translation, without affecting Atg16l1 mRNA stability. Circular RNA circPABPN1 blocked HuR binding to Atg16l1 mRNA and lowered ATG16L1 production. HuR silencing in cultured IECs also prevented rapamycin-induced autophagy, which was abolished by overexpressing ATG16L1. These findings indicate that HuR regulates autophagy by modulating ATG16L1 translation via interaction with circPABPN1 in the intestinal epithelium.

Pilot study on preventing anastomotic leakage in stapled gastroesophageal anastomosis.

BACKGROUND: This study explored how to improve the surgical technique to reduce or avoid anastomotic leakage. METHODS: From January 2012 to December 2016, 101 consecutive patients with cancer of the esophagus or gastroesophageal junction underwent stapled gastroesophageal anastomosis. The procedure included creating a tube-type stomach, fixing an inserted anvil, inspecting mucosa-to-mucosa alignment in the lumen under direct vision after firing the stapler, and, if found, manually repairing a rupture of the mucous membrane of the anastomosis. RESULTS: A rupture of the mucous membrane of the anastomosis was found in four out of the 101 patients and manually repaired. No postsurgical anastomotic leakage occurred. All patients recovered well and the average postoperative stay was 10.4 days. There was no mortality within 30 days after surgery. CONCLUSION: It is critical to inspect the integrality of the luminal mucous membrane of the anastomosis under direct vision in order to prevent anastomotic leakage in surgical resection of esophageal and gastroesophageal junction malignancies.

[A Programmed Procedure of Prosthetic Reconstruction of the Superior Vena Cava 
for Thoracic Tumors via Median Thoracotomy].

BACKGROUND: The involvement of superior vena cava is a common condition in locally advanced thoracic tumors. Patients may benefit from the high risk operation. This study proposed a programmed procedure to optimize surgical techniques, which can facilitate the safety of operation via median thoracotomy. METHODS: A total of 35 patients with thoracic disease involved superior vena cava underwent prosthetic vascular reconstruction via median thoracotomy. All patients were confirmed locally advanced without distant metastasis including 16 pulmonary neoplasm and 19 mediastinal disease. The operations proceed from left to right with one direction manner. The initial part of the left innominate vein was dissected, then cut off, so as to lift tumor, the pericardium was opened, and the left innominate vein and the right artrium were bridged with prosthetic vascular. The proximal end of the superior vena cava which not invaded was dissected and the tumor was pulled to the caudal side, the right mediastinal pleura was opened and the right inner mammary vascular was ligated and the right innominate vein was fully revealed. Stretch the tumor to left top, cut azygos vein on above the hilum, then block the right innominate vein and superior vena cava, removed involved part of blood vessels, the right innominate vein and superior vena cava was connected with prosthetic vascular. With these procedures the superior vena cava was reconstructed completely. RESULTS: The operation was completed successfully in all cases. Postoperative complications included 6 cases with arrhythmia, 5 cases with hypoxemia, 1 case with myasthenia crisis, 1 case with cardiac hernia, and 2 cases with fungal infection. 2 patients died of myocardial infarction and lung infection respectively with a mortality rate of 5.12%. The remaining 33 cases were discharged successfully. The average postoperative hospital stay was 15 days. Of the 10 patients with superior vena cava syndrome preoperatively, 8 patients had symptoms relief except 2 cases with intraoperative intravascular thrombosis. CONCLUSIONS: We recommended the programmed procedure of prosthetic reconstruction of the superior vena cava, standardize the details of treatment, and minimize the risk during operation. The safe surgical procedures of this group of cases confirm this practice.

[Progress on the Therapeutic Approaches for Malignant Tumor 
with Superior Vena Cava Syndrome].

Patients with thoracic malignant tumors often suffered from superior vena cava syndrome (SVCS), featured by high morbidity and mortality. Traditionally treated with palliative approaches, SVCS has been widely studied and novel therapeutic approaches have been investigated, focusing on drug therapy, interventional therapy, radiation therapy, surgery and proton therapy. In this manuscript, the progress of therapeutic approaches for SVCS is summarized.

[Complete Single-Utility-Port Thoracoscopic Resection of Lung Cancer 
with Single-Rib Metastasis].

BACKGROUND: Complete thoracoscopic surgery has advanced, and its indication has also been extended to complex procedures. The aim of this study is to investigate the feasibility of complete single-utility-port thoracoscopic lobectomy with rib resection. METHODS: A patient was diagnosed with lung cancer and single-rib metastasis. The patient received lobectomy and segment costectomy through complete single-utility-port thoracoscopic surgery. The literature was also reviewed. RESULTS: The tumor was staged at T1N1M1. The patient made an uneventful recovery and was dismissed on day 4 after surgery. At the last follow-up, the patient was alive and well, with no evidence of the disease at 18 months postoperatively. CONCLUSIONS: Highly selected cases of lung cancer with single-rib metastasis are appropriate candidates for complete single-utility-port thoracoscopic resection.

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells.

Paxillin (PXN) encodes a 68-kDa focal adhesion-associated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 normal adjacent tissues was performed, which showed that the positive rate of PXN was significantly higher in the colorectal adenocarcinoma samples than that in the normal colorectal mucosa samples (P<0.001). Moreover, PXN presence was also positively correlated with TNM stage (P=0.023), distant metastasis (P=0.014), recurrence (P=0.032) and reduced survival (P=0.004). In vitro, PXN expression was positively correlated with the proliferation rate in colorectal cells insensitive to cetuximab. Inhibition of PXN expression by PXN-siRNA clearly increased apoptosis by downregulating the phosphorylation of extracellular signal regulated kinase (p-Erk) level, and overexpression of PXN by PXN-cDNA decreased apoptosis by upregulating the p-Erk level. This suggests that overexpression of PXN could be one of the reasons for cetuximab resistance, and downregulation of PXN plays an important role in improving sensitivity to cetuximab by suppressing the activitation of p-Erk in colorectal cancer cells. Above all, knockdown of PXN could represent a rational therapeutic strategy for increasing the sensitivity or overcoming cetuximab-resistance in patients with colorectal cancer.

Targeting HCCR expression resensitizes gastric cancer cells to chemotherapy via down-regulating the activation of STAT3.

The human cervical cancer oncogene (HCCR) has been found to be overexpressed in a variety of human cancers. However, the level of expression of HCCR and its biological function in gastric cancer are largely unknown. In this study, we evaluated HCCR expression in several gastric cancer cell lines and in one normal gastric mucosal cell line. We established a 5-FU-resistant gastric cancer cell subline, and we evaluated its HCCR expression. HCCR expression levels were high in gastric cancer lines, and expression was significantly increased in the 5-FU-resistant cancer cell subline. HCCR expression affected cell growth by regulating apoptosis in the cancer cells, and it had a positive correlation with p-STAT3 expression. Western blot and luciferase reporter assays showed that the activation of STAT3 upregulated HCCR expression in a positive feedback loop model. In vivo and in vitro studies showed that HCCR plays an important role in the apoptosis induced by 5-FU. Our data demonstrate that HCCR is probably involved in apoptosis and cancer growth and that it functions as a p-STAT3 stimulator in a positive feedback loop model. In gastric cancer cells, HCCR confers a more aggressive phenotype and resistance to 5-FU-based chemotherapy.