Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC. AIM: To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC. METHODS: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated. RESULTS: The gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic. CONCLUSION: CLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.

Genome-wide identification and molecular evolution analysis of the heat shock transcription factor (HSF) gene family in four diploid and two allopolyploid Gossypium species.

Heat shock transcription factors (HSFs) can regulate plant development and stress response. The comprehensive evolutionary history of the HSF family remains elusive in cotton. In this study, each cotton species had 78 members in Gossypium barbadense and Gossypium hirsutum. The diploid species had 39 GaHSFs in Gossypium arboreum, 31 GrHSFs in Gossypium raimondii, 34 GtHSFs in Gossypium turneri, and 34 GlHSFs in Gossypium longicalyx. The HSF family in cotton can be classified into three subfamilies, with seven groups in subfamily A and five groups in subfamily B. Different groups exhibited distinct gene proportions, conserved motifs, gene structures, expansion rates, gene loss rates, and cis-regulatory elements. The paleohexaploidization event led to the expansion of the HSF family in cotton, and the gene duplication events in six Gossypium species were inherited from their common ancestor. The HSF family in diploid species had a divergent evolutionary history, whereas two cultivated tetraploids presented a highly conserved evolution of the HSF family. The HSF members in At and Dt subgenomes of the cultivated tetraploids showed a different evolution from their corresponding diploid donors. Some HSF members were regarded as key candidates for regulating cotton development and stress response. This study provided the comprehensive information on the evolutionary history of the HSF family in cotton.

Molecular Evolution and Expansion of the KUP Family in the Allopolyploid Cotton Species Gossypium hirsutum and Gossypium barbadense.

The comprehensive analysis of gene family evolution will elucidate the origin and evolution of gene families. The K+ uptake (KUP) gene family plays important roles in K+ uptake and transport, plant growth and development, and abiotic stress responses. However, the current understanding of the KUP family in cotton is limited. In this study, 51 and 53 KUPs were identified in Gossypium barbadense and Gossypium hirsutum, respectively. These KUPs were divided into five KUP subfamilies, with subfamily 2 containing three groups. Different subfamilies had different member numbers, conserved motifs, gene structures, regulatory elements, and gene expansion and loss rates. A paleohexaploidization event caused the expansion of GhKUP and GbKUP in cotton, and duplication events in G. hirsutum and G. barbadense have happened in a common ancestor of Gossypium. Meanwhile, the KUP members of the two allopolyploid subgenomes of G. hirsutum and G. barbadense exhibited unequal gene proportions, gene structural diversity, uneven chromosomal distributions, asymmetric expansion rates, and biased gene loss rates. In addition, the KUP families of G. hirsutum and G. barbadense displayed evolutionary conservation and divergence. Taken together, these results illustrated the molecular evolution and expansion of the KUP family in allopolyploid cotton species.

LRP4 promotes migration and invasion of gastric cancer under the regulation of microRNA-140-5p.

BACKGROUND: Low-density lipoprotein receptor-related protein 4 (LRP4) has been reported to be implicated in multiple types of cancers. However, the significance of LRP4 in gastric cancer (GC) remains poorly elucidated. Therefore, it's urgent to investigate the importance and underlying mechanisms of LRP4 in GC. OBJECTIVE: To investigate the clinical roles of LRP4 in GC. METHODS: The LRP4 mRNA and miR-140-5p was measured by qRT-PCR. The protein expression was determined Western blot. Kaplan-Meier survival curves and Cox proportional hazard regression models were performed to evaluate prognosis. RESULTS: We demonstrated that LRP4 mRNA and protein was up-regulated in GC tissues for the first time. Its high expression was significantly correlated with malignant clinical features including TNM stage and lymph-node metastasis and poor prognosis for GC patients. LRP4 promotes migration, invasion and epithelial-mesenchymal transition (EMT) progress of GC cells. Mechanically, LRP4 regulated PI3K/AKT in GC cells. AKT inhibitors reversed the effects of LRP4. Finally, LRP4 was regulated by miR-140-5p in GC. CONCLUSIONS: Our findings showed that LRP4 has an important function in GC progression and promotes GC migration, invasion and EMT by regulating PI3K/AKT under regulation of miR-140-5p, providing a potential therapeutic target for GC.

Pervasive duplication, biased molecular evolution and comprehensive functional analysis of the PP2C family in Glycine max.

BACKGROUND: Soybean (Glycine max) is an important oil provider and ecosystem participant. The protein phosphatase 2C (PP2C) plays important roles in key biological processes. Molecular evolution and functional analysis of the PP2C family in soybean are yet to be reported. RESULTS: The present study identified 134 GmPP2Cs with 10 subfamilies in soybean. Duplication events were prominent in the GmPP2C family, and all duplicated gene pairs were involved in the segmental duplication events. The legume-common duplication event and soybean-specific tetraploid have primarily led to expanding GmPP2C members in soybean. Sub-functionalization was the main evolutionary fate of duplicated GmPP2C members. Meanwhile, massive genes were lost in the GmPP2C family, especially from the F subfamily. Compared with other genes, the evolutionary rates were slower in the GmPP2C family. The PP2C members from the H subfamily resembled their ancestral genes. In addition, some GmPP2Cs were identified as the putative key regulator that could control plant growth and development. CONCLUSIONS: A total of 134 GmPP2Cs were identified in soybean, and their expansion, molecular evolution and putative functions were comprehensively analyzed. Our findings provided the detailed information on the evolutionary history of the GmPP2C family, and the candidate genes can be used in soybean breeding.

LncRNA IGFL2-AS1 functions as a ceRNA in regulating ARPP19 through competitive binding to miR-802 in gastric cancer.

Gastric cancer (GC) is one of the most common malignancies of the digestive system worldwide. Multiple long noncoding RNAs (lncRNAs) participate in the regulation of GC development and metastasis. In this study, we aimed to elucidate the expression and function of lncRNA IGFL2-AS1 in GC. We found that IGFL2-AS1 was highly expressed in GC tissues and cell lines. Knockdown of IGFL2-AS1 suppressed GC cell proliferation, migration, and invasion in vitro. Furthermore, we identified that IGFL2-AS1 exerted its function as a molecular sponge of miR-802. MiR-802 was demonstrated to be a tumor suppressor, and overexpression of miR-802 suppressed GC cell growth, migration, and invasion. Mechanistically, we revealed that the cAMP-regulated phosphoprotein 19 (ARPP19) was a direct target of miR-802 and could reverse the inhibitory function of miR-802. Moreover, our results confirmed that knockdown of IGFL2-AS1 inhibited GC tumor development in an in vivo GC tumor xenograft model. In summary, our data suggest that the IGFL2-AS1/miR-802/ARPP19 axis plays a critical role in the progression and metastasis of GC. Therapies targeting the IGFL2-AS1/miR-802/ARPP19 axis can potentially improve GC treatment.

Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating miRNAs.

Accumulating studies confirmed that luteolin, a common dietary flavonoid which is widely distributed in plants and has diverse beneficial biological function, including anti-oxidant, anti-inflammation and anticancer properties. However, the detail mechanisms of luteolin on GC are poorly understood. Here, we investigated the anticancer effect of luteolin in GC cells in vitro and in vivo. Luteolin reduced the cell viability in a time and dose-dependent manner. Luteolin significantly inhibited cell cycle progress, colony formation, proliferation, migration, invasion and promoted apoptosis in vitro and in vivo. Luteolin also regulated these biological effects associated regulators. Mechanically, luteolin treatment regulated Notch1, PI3K, AKT, mTOR, ERK, STAT3 and P38 signaling pathways and modulated a series of miRNAs expression. These findings provide novel insight into the molecular function of luteolin which suggest its potential as a therapeutic agent for human GC.

SYNJ2 variant rs9365723 is associated with colorectal cancer risk in Chinese Han population.

PURPOSE: Colorectal cancer (CRC) is the third most common cancer and fourth leading cause of cancer mortality, and twin studies have shown that approximately 35% of the variation in susceptibility to CRC involves inherited genetic differences. We sought to investigate potential genetic associations between some single nucleotide polymorphisms (SNPs) and the risk of CRC in the Chinese Han population. METHODS: We conducted a case-control study including 269 cases and 309 controls. Sixteen SNPs associated with CRC risk were selected from previous genome-wide association studies and genotyped using Sequenom MassARRAY technology. Odds ratios and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and gender. RESULTS: Using the chi-squared test we found that rs9365723 was associated with CRC risk (p = 0.012). With genetic model analysis, the genotype A/G-G/G (OR = 1.50; 95% CI 1.02-2.21; p = 0.038) of rs9365723 showed an increased risk of CRC in the dominant model. Furthermore, we found that rs9365723 was associated with an increased risk only for colon cancer but not rectal cancer (p = 0.009 and p = 0.414, respectively). CONCLUSIONS: Our results, combined with previous studies, suggest that rs9365723, located on SYNJ2, is associated with the risk of CRC in a Chinese population. Thus, SYNJ2 may play a role in the development of CRC, especially colon cancer.

[Efficacy comparison of laparoscopic versus open tension-free hernia repair using biologic mesh for inguinal strangulated hernia].

OBJECTIVE: To compare the efficacy of laparoscopic versus open tension-free mesh repair using biologic mesh for inguinal strangulated hernia. METHODS: Clinical data of 27 patients with inguinal strangulated hernia in the Shanxi Provincial People's Hospital between January 2012 and April 2014 were analyzed retrospectively. All the patients underwent one-stage tension-free repair using biological mesh, including laparoscopic(n=13) and open procedures(n=14). RESULTS: As compared with the open group, the laparoscopic group had shorter operative time [(90.8±11.6) min vs. (130.8±32.5) min, P<0.01], lower rates of hematoma/seroma and wound infection[(7.7% vs. 42.9%) and (0 vs. 28.6%) respectively, both P<0.05], faster recovery of bowel function [(2.5±0.3) d vs. (3.8±1.4) d, P<0.01], and shorter hospital stay [(6.3±1.8) d vs. (9.8±3.2) d, P<0.01]. The mean follow-up was 5.7 months (ranged from 2 to 12 months), and no recurrence or serious complications occurred. CONCLUSION: Laparoscopic tension-free hernia repair using biological mesh for inguinal strangulated hernia has significant advantage versus open operation.

Genetic mutations in human rectal cancers detected by targeted sequencing.

Colorectal cancer (CRC) is widespread with significant mortality. Both inherited and sporadic mutations in various signaling pathways influence the development and progression of the cancer. Identifying genetic mutations in CRC is important for optimal patient treatment and many approaches currently exist to uncover these mutations, including next-generation sequencing (NGS) and commercially available kits. In the present study, we used a semiconductor-based targeted DNA-sequencing approach to sequence and identify genetic mutations in 91 human rectal cancer samples. Analysis revealed frequent mutations in KRAS (58.2%), TP53 (28.6%), APC (16.5%), FBXW7 (9.9%) and PIK3CA (9.9%), and additional mutations in BRAF, CTNNB1, ERBB2 and SMAD4 were also detected at lesser frequencies. Thirty-eight samples (41.8%) also contained two or more mutations, with common combination mutations occurring between KRAS and TP53 (42.1%), and KRAS and APC (31.6%). DNA sequencing for individual cancers is of clinical importance for targeted drug therapy and the advantages of such targeted gene sequencing over other NGS platforms or commercially available kits in sensitivity, cost and time effectiveness may aid clinicians in treating CRC patients in the near future.

DUSP10 gene polymorphism and risk of colorectal cancer in the Han Chinese population.

Dual-specificity protein phosphatases (DUSP) negatively regulate members of the mitogen-activated protein kinase superfamily, which is associated with cellular proliferation and differentiation. A recent study suggests that DUSP10 is frequently upregulated in colorectal cancer (CRC). Our study aimed to assess whether DUSP10 contributes to the risk of CRC. We analyzed nine tag single nucleotide polymorphisms (tSNPs) of DUSP10 in a case-control study of Han Chinese by the χ²-test and the SHEsis software. We found that two tSNPs (rs908858, P=0.00004; rs11118838, P=0.02510) were significantly associated with CRC using the χ²-test. Using the SHEsis software, six tSNPs (rs12041033, rs17010629, rs12724393, rs12036163, rs11118838, rs12044821) were found in the same linkage disequilibrium block. Within this linkage disequilibrium block, haplotype 'CTCAAC' showed an increased risk of CRC by 42%. By global haplotype analysis, we found that the haplotype 'ACTCAACTA' may increase the risk of CRC by ∼53%; the haplotype 'GCCCACCCA' may decrease the risk by ∼46%. Our results, combined with previous studies, suggest that certain mutations in DUSP10 correlate with the incidence of CRC. Thus, the function of the DUSP10 gene product may contribute toward CRC in the Han Chinese population.