Gemcitabine is the first-line chemotherapeutic agent for advanced adenocarcinoma of the pancreas; however, chemoresistance to gemcitabine remains a major cause of failure for the clinical treatment of this disease. Polo-like kinase 1 (Plk-1) is highly expressed in pancreatic cancer cell lines and pancreatic tumour tissues, and is involved in a wide variety of cell cycle processes. Nevertheless, its biological role and implication for gemcitabine resistance are not clearly defined. In this study, we used RNA-interference (RNAi)-mediated depletion of Plk-1 to determine its potential for sensitizing pancreatic tumour cells to gemcitabine. We showed that the level of Plk-1 protein was correlated significantly with gemcitabine resistance in human pancreatic adenocarcinoma cells and that overexpression of Plk-1 reduced sensitivity to gemcitabine in these cells. In addition, small interfering RNA (siRNA)-mediated knockdown of Plk-1 caused cell cycle arrest at G2/M and the reduction of cellular proliferation. More importantly, the treatment of pancreatic cancer cells with Plk-1 siRNA followed by exposure to gemcitabine dramatically decreased cell viability and increased cellular apoptosis, as compared with treatment with either agent alone. These observations indicate that down-regulation of Plk-1 expression by RNAi enhances gemcitabine sensitivity and increases gemcitabine cytotoxicity in pancreatic tumour cells. This is the first demonstration that the combination of Plk-1 gene therapy and gemcitabine chemotherapy has synergistic anti-tumour activity against pancreatic carcinoma in vitro. This combination treatment warrants further investigation as an effective therapeutic regimen for patients with resistant pancreatic cancer and other tumours.

Studies of both, microbiota and target therapy associated with gene mutations in colorectal cancer, (CRC) have attracted increasing attention. However, only a few of them analyzed the combined effects on CRC. we analyzed differences in intestinal microbiota of 44 colorectal cancer patients and 20 healthy controls (HC) using 16S rRNA gene sequencing of fecal samples. For 39 of the CRC patients, targeted Next Generation Sequencing (NGS) was carried out at formalin fixed paraffin embedded (FFPE) samples to identify somatic mutation profiles. Compared to the HC group, the microbial diversity of CRC patients was significantly lower. In the CRC group, we found a microbiome that was significantly enriched for strains of Bifidobacterium, Bacteroides, and Megasphaera whereas in the HC group the abundance of Collinsella, Faecalibacterium, and Agathobacter strains was higher. Among the mutations detected in the CRC group, the APC gene had the highest mutation rate (77%, 30/39). We found that the KRAS mutant type was closely associated with Faecalibacterium, Roseburia, Megamonas, Lachnoclostridium, and Harryflintia. Notably, Spearman correlation analysis showed that KRAS mutations were negatively correlated with the existence of Bifidobacterium and positively correlated with Faecalibacterium. By employing 16S rRNA gene sequencing, we identified more unique features of microbiota profiles in CRC patients. For the first time, our study showed that gene mutations could directly be linked to the microbiota composition of CRC patients. We hypothesize that the effect of a targeted colorectal cancer therapy is also closely related to the colorectal flora, however, this requires further investigation.

Background: Inflammatory cellular response is implicated in the pathogenesis of colorectal cancer (CRC). Nevertheless, the dynamic effects of inflammatory index coNLR (neutrophil-to-lymphocyte ratio)-PLR (platelet-to-lymphocyte ratio) during chemotherapy remain elusive. Methods: The baseline clinical data and laboratory parameters of 480 CRC patients who received palliative resection of primary tumors and FOLFOX-based chemotherapy from January 2007 to January 2013 were retrospectively analyzed. Receiver operating characteristic curves were plotted to obtain the predictive NLR and PLR values, and to calculate the coNLR-PLR score. The Kaplan–Meier method was used to estimate the rates of recurrence-free survival (RFS) and overall survival (OS), and the Cox proportional hazards model was employed for analysis. Results: The dynamic cut-off values of NLR during four periods of chemotherapy were 3.029, 2.466, 2.102 and 1.795, respectively, and those of PLR were 216.438, 187.572, 169.027 and 174.368, respectively. A higher coNLR-PLR was significantly associated with lower rates of RFS and OS ( P <0.05). Both univariate and multivariate analyses showed that coNLR-PLR was a significant independent prognostic factor for RFS and OS ( P <0.05). Conclusions: CoNLR-PLR was a significant prognostic predictor for CRC patients who received FOLFOX-based chemotherapy. Evaluating this index can accurately predict the clinical treatment outcomes after chemotherapy.

Background: Colon cancer (CC) is the most commonly occurring malignant tumor in the world. The current cancer treatment options have been less effective especially in the advanced stages of CC and patients have poor overall survival. Hence, there is an urgent need to explore novel molecular therapeutic targets for CC treatment. Methods: qRT-PCR was performed to detect the levels of lncRNA LINC01224 (LINC01224), microRNA-485-5p (miR-485-5p), MCL1 in CC tumor tissues or cell lines. Two si-RNAs against LINC01224 were used to silence the level of LINC01224, and CCK-8 assay, colony formation assay, and transwell assay were performed to explore the role of LINC01224 on the proliferation, migration, and invasion of CC cell lines. Kaplan-Meier method was applied for evaluating the association between LINC01224 level and the overall survival of CC patients. Through bioinformatics analysis, we found that LINC01224 sponged miR-485-5p and consequently targeted MCL1. Dual-luciferase reporter assay, RNA pulldown assay, qRT-PCR, and Western blot assay were conducted for verification of the interactions among LINC01224, miR-485-5p, and MCL1. Furthermore, the role of LINC01224/miR-485-5p/MCL1 axis in CC progression was investigated by CCK-8 assay, colony formation assay, and transwell assay. Results: LINC01224 was highly expressed in CC tumor tissues and CC cell lines, and its expression was associated with the overall survival of CC patients. The LINC01224-siRNAs (si-LINC01224) markedly suppressed the level of LINC01224 in CC cell lines (HT29 and SW480 cells) and consequently significantly suppressed the proliferation, migration, and invasion of the HT29 and SW480 cells. LINC01224 was verified to sponge miR-485-5p and consequently targeted MCL1. MiR-485-5p inhibitor or MCL1 overexpression (MCL1 OE) markedly restored the repressive effect of the si-LINC01224 pool on MCL1 expression level, as well as proliferation, migration, and invasion of HT29 and SW480 cells. Conclusion:This study identified LINC01224/miR-485-5p/MCL1 axis as a novel molecular therapeutic target involved in CC progression.

Background: Laminin subunit betas (LAMBs) are the major noncollagenous constituent of basement membranes that implicated in biological functions such as cell adhesion, metastasis. However, few studies have systematically analyzed the prognostic value and immune characteristics of LAMBs in pan-cancer types. Methods: A pan-cancer comprehensive analysis of LAMBs in expression levels, protein localization, structure, mutations and methylation were explored. Next, Cox regression and Kaplan-Meier method were applied to analyze the prognostic role of LAMBs in pan-cancer. Protein-Protein Interaction (PPI) analysis was performed in the GeneMANIA database, and enrichment analysis was predicted signaling pathways were identifified by using Gene Ontology (GO), Kyoto Encyclopedia of Genes (KEGG) and gene set variation analysis (GSVA) analysis. The immune characteristics of LAMBs in the tumor microenvironment were evaluated via ImmuCellAI and TIMER 2.0. was the main platform to investigate the tumor associated macrophages (TAMs) related to LAMBs in pan-cancer, especially M2-like TAMs. In addition, single-cell sequencing analysis and tracking tumor immunophenotype (TIP) were also conducted to validate the interaction immune role of LAMBs with macrophages in cancers. Furthermore, the immunoregulators, tumour mutational burden (TMB) and microsatellite instability (MSI) was performed to evaluate the immune response role of LAMBs in cancers. Finally, the immunotherapy response and drug sensitive small molecule drugs based on LAMBs expression were predicted. Results: The expression, mutation and methylation of LAMBs was aberrantly expressed in most cancer types and exhibited prognosis predictive ability in various cancers. In addition, our results also showed that LAMBs was signifificantly correlated with immune-activated (including pathways and biological processes), immune cell infifiltrations, immunoregulator expressions, TMB and MSI. Importantly, analysis of an independent immunotherapy cohorts revealed that low-risk patients had better immunotherapy responses and prognosis than high-risk patients in some cancers. Furthermore, the immunotherapy response and sensitive small molecule drugs which correlate with LAMBs expression in different cancer types, had a potent capability to predict immunotherapy response in pan-cancers. Conclusions: LAMBs expression may contribute to increased infiltration of TAMs, which not only acted as a potent prognostic factor to predict the clinical outcomes of cancer patients but was also a promising immunotherapy predictive biomarker for cancer patients treated with immune-checkpoint inhibitors (ICIs).