Loss of RBM45 inhibits breast cancer progression by reducing the SUMOylation of IRF7 to promote IFNB1 transcription.

Type I interferons exhibit anti-proliferative and anti-cancer activities, but their detailed regulatory mechanisms in cancer have not been fully elucidated yet. RNA binding proteins are master orchestrators of gene regulation, which are closely related to tumor progression. Here we show that the upregulated RNA binding protein RBM45 correlates with poor prognosis in breast cancer. Depletion of RBM45 suppresses breast cancer progression both in cultured cells and xenograft mouse models. Mechanistically, RBM45 ablation inhibits breast cancer progression through regulating type I interferon signaling, particularly by elevating IFN-ß production. Importantly, RBM45 recruits TRIM28 to IRF7 and stimulates its SUMOylation, thereby repressing IFNB1 transcription. Loss of RBM45 reduced the SUMOylation of IRF7 by reducing the interaction between TRIM28 and IRF7 to promote IFNB1 transcription, leading to the inhibition of breast cancer progression. Taken together, our finding uncovers a vital role of RBM45 in modulating type I interferon signaling and cancer aggressive progression, implicating RBM45 as a potential therapeutic target in breast cancer.

RBMS1 Coordinates with the m6A Reader YTHDF1 to Promote NSCLC Metastasis through Stimulating S100P Translation.

Metastasis is the leading cause for the high mortality of lung cancer, however, effective anti-metastatic drugs are still limited. Here it is reported that the RNA-binding protein RBMS1 is positively associated with increased lymph node metastasis in non-small cell lung cancer (NSCLC). Depletion of RBMS1 suppresses cancer cell migration and invasion in vitro and inhibits cancer cell metastasis in vivo. Mechanistically, RBMS1 interacts with YTHDF1 to promote the translation of S100P, thereby accelerating NSCLC cell metastasis. The RRM2 motif of RBMS1 and the YTH domain of YTHDF1 are required for the binding of RBMS1 and YTHDF1. RBMS1 ablation inhibits the translation of S100P and suppresses tumor metastasis. Targeting RBMS1 with NTP, a small molecular chemical inhibitor of RBMS1, attenuates tumor metastasis in a mouse lung metastasis model. Correlation studies in lung cancer patients further validate the clinical relevance of the findings. Collectively, the study provides insight into the molecular mechanism by which RBMS1 promotes NSCLC metastasis and offers a therapeutic strategy for metastatic NSCLC.

mTOR inhibitor introduce disitamab vedotin (RC48-ADC) rechallenge microtubule-chemotherapy resistance in HER2-low MBC patients with PI3K mutation.

This study aimed to explore the efficacy and potential mechanisms of rechallenge therapy with microtubule-targeting agents (MTAs) in patients with HER2-low metastatic breast cancer (MBC). We performed a systematic review to investigate the rechallenge treatment concept in the field of HER2-low MBC treatment and utilized a series of cases identified in the literature to illustrate the concept. Here we reported two clinical cases of HER2-low MBC patients whose disease progressed after prior treatment with MTAs such as docetaxel and vincristine. When rechallenged with disitamab vedotin ((RC48-antibody-drug conjugate (ADC), a monomethyl auristatin (MMAE) MTA)), both patients achieved a partial response and the final progression-free survival (PFS) was 13.5 and 9 months, respectively. Genomic profiling detected a PIK3CA H1047R mutation in the patients. The patients were treated with everolimus before being rechallenged with RC48, which may lead to a better response. This study further summarizes and analyzes the potential mechanism of the PI3K-AKT signaling pathway in MTA resistance and reveals that the PIK3CA H1047R mutation may be a potential molecular marker for the efficacy prediction of mTOR inhibitors, providing new insights and potential therapeutic strategies for the application of MTAs to MBC patients.

The influence of health literacy and knowledge about smoking hazards on the intention to quit smoking and its intensity: an empirical study based on the data of China's health literacy investigation.

OBJECTIVE: This study explored the relationship between smokers' health literacy, knowledge of smoking hazards, and their intention to quit. METHODS: Based on data from the 2019 Health Literacy and Tobacco Use Surveillance among residents of a city in Zhejiang Province, 1120 male smokers were screened. Differential tests were used to analyze whether smokers with varying levels of health literacy and knowledge about smoking hazards differed in their intention to quit smoking and the intensity of their intention. A multi-factor logistic regression model was constructed to explore the extent of these differences. RESULTS: Only 24.8% of smokers had higher health literacy. Among smokers, those with an intention to quit had a higher health literacy level compared to those without such intention (32.7% vs. 17.0%, p < 0.001). Health literacy levels did not differ significantly between groups with different intensity of intention to quit (34.2% vs. 31.9% vs. 30.1%, p = 0.435). About 48.7% of the smokers a higher level of knowledge about smoking hazards. It was more prevalent in the intent to quit group compared to the no intent to quit group (54.0% vs. 43.4%, p < 0.001), and the low intent to quit group had lower knowledge compared to the moderate and high intent to quit groups (49.1% vs. 56.6% vs. 63.4%, p = 0.011). After adjusting for other influences, smokers with lower health literacy were less likely to have intention to quit (OR = 0.659, p = 0.016). And the association between knowledge about smoking hazards and whether smokers have the intention to quit is no longer significant, but it significantly affects the intensity of the intention to quit among smokers who already have the intention (OR = 0.623, p = 0.005). CONCLUSION: General health literacy may play a role in facilitating smokers' progression from the stage of no intent to quit to one of intent to quit, but a more specific understanding of the harms of smoking may be needed to increase the strength of intent to quit.

A Novel Clinical Prognostic Model for Breast Cancer Patients with Malignant Pleural Effusion: Avoiding Chemotherapy in Low-Risk Groups?

Purpose: Malignant pleural effusion (MPE) is a severe complication in patients with advanced cancer that is associated with a poor prognosis. Breast cancer is the second leading cause of MPE after lung cancer. We therefore aim to describe clinical characteristics of the patients with MPE combined with breast cancer and construct a machine learning-based model for predicting the prognosis of such patients. Methods: This study is a retrospective and observational study. Least absolute shrinkage and selection operator (LASSO) and univariate Cox regression analyses were applied to identify eight key clinical variables, and a nomogram model was established. Model performance was evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analyses. Results: 196 patients with both MPE and breast cancer (143 in the training group and 53 in the ex-ternal validation group) were analyzed in this study. The median overall survival in two cohorts was 16.20 months and 11.37 months. Based on the ROC curves for 3-, 6-, and 12-month survival, the areas under the curves were 0.824, 0.824, and 0.818 in the training set and 0.777, 0.790, and 0.715 in the validation set, respectively. In the follow-up analysis, both systemic and intrapleural chemotherapy significantly increased survival in the high-risk group compared to the low-risk group. Conclusion: Collectively, MPE confers a poor prognosis in breast cancer patients. We have developed a first-ever survival prediction model for breast cancer patients with newly diagnosed MPE and validated the model using an independent cohort.

RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis.

Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors. However, the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive. Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma (ESCC) cells by dictating the activity of LKB1, a critical governor of cancer metabolism. The level of RBM4 was specifically elevated in ESCC compared to normal tissues, and RBM4 overexpression promoted the malignant phenotype. RBM4 contributed to overcome H-RAS- or doxorubicin-induced senescence, while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade. Mechanistically, RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, subsequently recruiting the E3 ligase TRIM26 to LKB1, promoting LKB1 ubiquitination and degradation in nucleus. Therefore, such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism. Clinically, the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1. The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839, providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.

Influence of health literacy on health outcomes of different social strata-- an empirical study based on the data of China's health literacy investigation.

BACKGROUND: Health literacy has always been considered as an important factor to promote people's health, but does it have a significant effect on health across all social strata and especially lower social strata? This study aims to analyze the influences of health literacy on health outcomes of different social strata, and then infer whether improving health literacy can reduce health disparities among different social strata. METHODS: Utilizing health literacy monitoring data from a city in Zhejiang Province in 2020, the samples are divided into three social strata according to the socioeconomic status score: low, middle and high social stratum, to compare whether there are significant differences in health outcomes between population with lower and higher health literacy among different social strata. In the strata with significant differences, control the confounding factors to further verify the influence of health literacy on health outcomes. RESULTS: In low and middle social strata, there are significant differences between population with lower and higher health literacy, when considering the two types of health outcomes (chronic diseases and self-rated health), but in high social stratum, this difference is not significant. After controlling the relevant variables, the influence of health literacy on the prevalence of chronic diseases is statistically significant only in low social stratum, and the health literacy is negatively correlated with the prevalence of chronic diseases(OR = 0.722, P = 0.022). In addition, there are statistical significances for positive impact of health literacy on self-rated health in both low and middle social strata (OR = 1.285, P = 0.047; OR = 1.401, P = 0.023). CONCLUSION: Compared with high social stratum, the influence of health literacy on health outcomes of low social stratum (chronic diseases) or both middle and low social strata (self-rated health) is more significant, and both are to improve the health outcomes. This finding suggests that improving residents' health literacy may be an effective way to alleviate the health disparities among different social strata.

Interfacial S-O bonds specifically boost Z-scheme charge separation in a CuInS2/In2O3 heterojunction for efficient photocatalytic activity.

Reducing the recombination rate of photoexcited electron-hole pairs is always a great challenging work for the photocatalytic technique. In response to this issue, herein, a novel Z-scheme CuInS2/In2O3 with interfacial S-O linkages was synthesized by a hydrothermal and subsequently annealing method. The Fourier transform infrared (FT-IR) and X-ray photoelectron spectrometer (XPS) measurements confirmed the formation of covalent S-O bonds between CuInS2 and In2O3. The quenching and electron spin resonance (ESR) tests revealed the Z-scheme transfer route of photogenerated carriers over the CuInS2/In2O3 heterojunctions, which was further verified theoretically via density functional theory (DFT) calculations. As expected, the CuInS2/In2O3 heterojunctions showed significantly boosted photocatalytic activities for lomefloxacin degradation and Cr(vi) reduction under visible light illumination compared with the bare materials. Accordingly, a synergistic photocatalytic mechanism of Z-scheme heterostructures and interfacial S-O bonding was proposed, in which the S-O linkage could act as a specific bridge to modify the Z-scheme manner for accelerating the interfacial charge transmission. Furthermore, the CuInS2/In2O3 heterojunction also exhibited excellent performance perceived in the stability and reusability tests. This work provides a new approach for designing and fabricating novel Z-scheme heterostructures with a high-efficiency charge transfer route.

Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO.

Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tumor growth through regulating RNA alternative splicing remains largely unknown. Here we demonstrated that melatonin could inhibit the growth of HCC. Mechanistically, melatonin induced transcriptional alterations of genes, which are involved in DNA replication, DNA metabolic process, DNA repair, response to wounding, steroid metabolic process, and extracellular matrix functions. Importantly, melatonin controlled numerous cancer-related RNA alternative splicing events, regulating mitotic cell cycle, microtubule-based process, kinase activity, DNA metabolic process, GTPase regulator activity functions. The regulatory effect of melatonin on alternative splicing is partially mediated by melatonin receptor MT1. Specifically, melatonin regulates the splicing of IKBKG (NEMO), an essential modulator of NF-κB. In brief, melatonin increased the production of the long isoform of NEMO-L with exon 5 inclusion, thereby inhibiting the growth of HepG2 cells. Collectively, our study provides a novel mechanism of melatonin in regulating RNA alternative splicing, and offers a new perspective for melatonin in the inhibition of cancer progression.

Salvia chinensis Benth Inhibits Triple-Negative Breast Cancer Progression by Inducing the DNA Damage Pathway.

Objective: Triple-negative breast cancer (TNBC) is distinguished by early recurrence and metastases, a high proclivity for treatment resistance, and a lack of targeted medicines, highlighting the importance of developing innovative therapeutic techniques. Salvia chinensis Benth (SCH) has been widely studied for its anticancer properties in a variety of cancers. However, its significance in TNBC treatment is rarely discussed. Our study investigated the anticancer effect of SCH on TNBC and the underlying mechanisms. Methods: First, we used clonogenic, cell viability, flow cytometry, and Transwell assays to assess the effect of SCH on TNBC. Bioinformatic studies, especially network pharmacology-based analysis and RNA sequencing analysis, were performed to investigate the constituents of SCH and its molecular mechanisms in the suppression of TNBC. High-performance liquid chromatography and thin-layer chromatography were used to identify two major components, quercetin and ß-sitosterol. Then, we discovered the synergistic cytotoxicity of quercetin and ß-sitosterol and assessed their synergistic prevention of cell migration and invasion. Breast cancer xenografts were also created using MDA-MB-231 cells to test the synergistic therapeutic impact of quercetin and ß-sitosterol on TNBC in vivo. The impact on the DNA damage and repair pathways was investigated using the comet assay and Western blot analysis. Results: Our findings showed that SCH decreased TNBC cell growth, migration, and invasion while also inducing cell death. We identified quercetin and ß-sitosterol as the core active components of SCH based on a network pharmacology study. According to RNA sequencing research, the p53 signaling pathway is also regarded as a critical biological mechanism of SCH treatment. The comet assay consistently showed that SCH significantly increased DNA damage in TNBC cells. Our in vivo and in vitro data revealed that the combination of quercetin and ß-sitosterol induced synergistic cytotoxicity and DNA damage in TNBC cells. In particular, SCH particularly blocked the inter-strand cross-link repair mechanism and the double-strand breach repair caused by the homologous recombination pathway, in addition to inducing DNA damage. Treatment with quercetin and ß-sitosterol produced similar outcomes. Conclusion: The current study provides novel insight into the previously unknown therapeutic potential of SCH as a DNA-damaging agent in TNBC.

Prognostic value of baseline genetic features and newly identified TP53 mutations in advanced breast cancer.

Approximately 30% of breast cancer (BC) patients suffer from disease relapse after definitive treatment. Monitoring BC at baseline and disease progression using comprehensive genomic profiling would facilitate the prediction of prognosis. We retrospectively studied 101 BC patients ultimately experiencing relapse and/or metastases. The baseline and circulating tumor DNA-monitoring cohorts included patients with baseline tumor tissue and serial plasma samples, respectively. Samples were analyzed with targeted next-generation sequencing of 425 cancer-relevant genes. Of 35 patients in the baseline cohort, patients with TP53 mutations (P < 0.01), or CTCF/GNAS mutations (P < 0.01) displayed inferior disease-free survival, and patients harboring TP53 (P = 0.06) or NOTCH1 (P = 0.06) mutations showed relatively poor overall survival (OS), compared to patients with wild-type counterparts. Of the 59 patients with serial plasma samples, 11 patients who were newly detected with TP53 mutations had worse OS than patients whose TP53 mutational status remained negative (P < 0.01). These results indicate that an inferior prognosis of advanced breast cancer was potentially associated with baseline TP53, CTCF, and NOTCH1 alterations. Newly identified TP53 mutations after relapse and/or metastasis was another potential prognostic biomarker of poor prognosis.

A novel treatment strategy of HER2-targeted therapy in combination with Everolimus for HR+/HER2- advanced breast cancer patients with HER2 mutations.

The incidence of HER2 somatic mutations in breast cancer is about 2-4%, mainly occurring in the HR+/HER2- subtype. Preclinical studies suggest that HER2 mutations can lead to constitutive HER2 activation, but effective treatment options for the clinical management of patients with HER2 mutations remain obscure. Our study analyzed HER2 mutation status by performing next-generation sequencing using tumor tissues and over 300 plasma samples from 72 metastatic breast cancer patients. We observed that two patients bearing HER2 mutations (Patient #1 bearing S310F and V777L mutations, Patient #2 bearing 778insGSP mutation) achieved a durable partial response to Trastuzumab combined with Everolimus. In vitro experiments showed that T47D and MCF7 cells overexpressing these HER2 mutants (S310F, V777L, 778insGSP and L755S) were sensitive to HER2-targeted therapies combined with the mTOR inhibitor Everolimus. These findings provide a treatment option for patients with HER2 mutations by combining HER2-targeted therapies with Everolimus.

A novel mutant PIK3R1EY451delinsD breast cancer patient resistant to HER2-targeted therapy treated with everolimus: a case report.

BACKGROUND: Resistance to HER2-targeted therapy is a critical issue in breast cancer that must be addressed immediately. PIK3R1 mutations are more common in Chinese breast cancer patients (17%, 25/147, Fudan University Shanghai Cancer Center FUSCC vs. 1.8%, 87/4602, TCGA all breast cancer studies). However, very limited information is available on the relationship between PIK3R1 mutation status and resistance to HER2-targeted therapies in patients with HER2-positive breast cancer. CASE REPORT: We present a case of a HER2-positive advanced breast cancer patient with the PIK3R1EY451delinsD mutation who developed resistance to HER2-targeted therapy and had a better response to everolimus combined with trastuzumab and carboplatin. CONCLUSIONS: To the best of our knowledge, this is the first study to show that the PIK3R1EY451delinsD mutation confers resistance to anti-HER2 therapy in breast cancer and that combining with everolimus treatment may overcome this resistance mechanism. We hypothesize that the PIK3R1EY451delinsD mutation is associated with the resistance to anti-HER2 therapy, and that this mutation merits further investigation as a clinical biomarker and therapeutic target.

Favorable Response to Olaparib in a Patient with Cancer of Unknown Primary Carrying a Germline BRCA1 R71K Mutation.

The treatment options for cancer of unknown primary (CUP) are challenging due to the lack of knowledge about the primary sites, often resulting in a poor prognosis. The emerging next-generation sequencing (NGS) technique has provided a reliable approach to facilitate tumor primary site prediction and targetable gene alteration identification for CUP patients. In this report, we described a 63-year-old female patient who experienced recurrent CUP. NGS-based genetic profiling results revealed a pathogenic germline BRCA1 R71K mutation. Accordingly, the patient received the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib treatment and demonstrated a favorable response to this treatment. Our case suggests that NGS holds great promise for providing improved diagnosis and treatment options to patients with CUP, warranting further clinical investigation.

Robust Fabrication of Fluorescent Cellulosic Materials via Hantzsch Reaction.

Hantzsch reaction is one of the typical multicomponent reactions (MCRs), and it is employed herein to endow cellulosic materials with fluorescent properties. For example, acetoacetyl (ACAC)-bearing cotton fabric prepared via transesterification with tert-butyl acetoacetate is subjected to an aqueous Hantzsch reaction with formaldehyde and ammonium acetate at ambient temperature. A strong fluorescent emission around 460 nm is achieved within 10 min. XPS, fluorescent spectroscopy, and elemental analysis are used to confirm the presence of 1,4-dihydropyridine (DHP) rings on the surface of the fabric. TGA, SEM, XRD, and mechanical testing results show that the modification process has minimum impact on intrinsic properties of the fabric. The strategy is also shown to be generally applicable to various forms of cellulosic materials and different aldehydes. This fast and simple approach enriches the application of MCR in modification of cellulose and cellulose derivatives.

The Effects of Gene Duplication Modes on the Evolution of Regulatory Divergence in Wild and Cultivated Soybean.

Regulatory changes include divergence in both cis-elements and trans-factors, which play roles in organismal evolution. Whole genome duplications (WGD) followed by diploidization are a recurrent feature in the evolutionary history of angiosperms. Prior studies have shown that duplicated genes have different evolutionary fates due to variable selection constraints and results in genomic compositions with hallmarks of paleopolyploidy. The recent sequential WGDs and post-WGD evolution in the common ancestor of cultivated soybean (Glycine max) and wild soybean (Glycine soja), together with other models of gene duplication, have resulted in a highly duplicated genome. In this study, we investigated the transcriptional changes in G. soja and G. max. We identified a sizable proportion of interspecific differentially expressed genes (DEGs) and found parental expression level dominance of G. max in their F1 hybrids. By classifying genes into different regulatory divergence types, we found the trans-regulatory changes played a predominant role in transcriptional divergence between wild and cultivated soybean. The same gene ontology (GO) and protein family (Pfam) terms were found to be over-represented in DEGs and genes of cis-only between JY47 and GS, suggesting the substantial contribution of cis-regulatory divergences to the evolution of wild and cultivated soybeans. By further dissecting genes into five different duplication modes, we found genes in different duplication modes tend to accumulate different types of regulatory differences. A relatively higher proportion of cis-only regulatory divergences was detected in singleton, dispersed, proximal, and tandem duplicates than WGD duplicates and genome-wide level, which is in line with the prediction of gene balance hypothesis for the differential fates of duplicated genes post-WGD. The numbers of cis-only and trans-only regulated genes were similar for singletons, whereas there were more genes of trans-only than cis-only in the rest duplication types, especially in WGD in which there were two times more trans-only genes than that in cis-only type. Tandem duplicates showed the highest proportion of trans-only genes probably due to some special features of this class. In summary, our results demonstrate that genes in different duplication modes have different fates in transcriptional evolution underpinned by cis- or trans-regulatory divergences in soybean and likely in other paleopolyploid higher organisms.

Refractive Index Sensor Based on Double Side-Polished U-Shaped Plastic Optical Fiber.

A U-shaped double-side polished plastic optical fiber (POF) is demonstrated as a liquid refractive index (RI) sensor. The refractive index of glycerinum solutions is identified by the intensity detection on the bending and evanescent wave loss change. Heat treatment and mechanical polishing are adopted to form the symmetrical side-polished POF probe. The processing parameters are experimentally optimized on the power transmittance. The sensitivity of 1541%/RIU (Refractive Index Unit) can be obtained with a resolution of 5.35 × 10-4 in the scope of 1.33-1.39. The favorable temperature characteristic is proved to offer stable RI sensing from 20 to 50 °C. This simple POF sensor has potentials in low-cost visible light intensity RI detection.

Screening potential microRNAs associated with pancreatic cancer: Data mining based on RNA sequencing and microarrays.

Pancreatic cancer is a malignant tumor of the digestive tract, rendering it difficult to make an accurate diagnosis. The 5 year survival rate for pancreatic cancer is <1%, and surgical resection rarely proves to be effective. Therefore, the identification of more effective methods for the early detection of pancreatic cancer is an urgent requirement. The present study aimed to explore key genes and microRNAs (miRNAs) associated with the pathogenesis of pancreatic cancer. Public databases were searched, and the data were integrated from The Cancer Genome Atlas and Gene Expression Omnibus databases, leading to the identification of 23 differentially expressed miRNAs (DE-miRNAs). A total of four of the DE-miRNAs were upregulated (hsa-miR-892b, hsa-miR-194-2, hsa-miR-200a and hsa-miR-194-1), whereas 19 downregulated DE-miRNAs (hsa-miR-424, hsa-miR-191, hsa-miR-484, hsa-miR-142, hsa-miR-15b, hsa-miR-450a-1, hsa-miR-423, hsa-miR-126, hsa-miR-505, hsa-miR-16-1, hsa-miR-342, hsa-miR-130a, hsa-miR-3613, hsa-miR-450a-2, hsa-miR-26b, hsa-miR-451, hsa-miR-19b-2, hsa-miR-106a and hsa-miR-503) were identified using the cut-off criteria of P<0.05 and |log 2FC|>1.0. Hsa-miR-3613-5p was identified as a prognostic DE-miRNA. The functional enrichment analyses demonstrated that the target genes of hsa-miR-3613-5p may be associated with the p53 signaling pathway. Survival analysis performed for genes in the p53 signaling pathway revealed that cyclin-dependent kinase 6 and ribonucleoside-diphosphate reductase subunit M2 may be the most likely to be associated with prognostic value. The integrated analysis performed in the current study demonstrated that hsa-miR-3613-5p may be used as a potential prognostic marker for pancreatic cancer.

Prognostic significance of LAPTM4B and p27kip1 expression in triple-negative breast cancer.

BACKGROUD: Triple-negative breast cancer (TNBC) is associated with an aggressive phenotype and poor prognosis, and the lack of druggable markers leads to the unavailability of targeted therapies. Thus, there is an urgent need to identify potential targets for triple-negative breast cancer. OBJECTIVE: In this study, we aimed to explore the expression of LAPTM4B and p27kip1 in triple-negative breast cancer, and its clinical significance. METHODS: We analyzed the expression and association of LAPTM4B and p27kip1 in human breast cancer databases. To analyze the role of LAPTM4B in the aggressiveness of the human triple-negative breast cancer, the expressions of LAPTM4B were knocked down in MDA-MB-231 and HCC1187 cell lines. Then, cell proliferation, migration and apoptosis were assessed in vitro. Furthermore, the immunohistochemistry examinations of LAPTM4B and p27kip1 expression were performed using surgical specimens from 188 primary triple-negative breast cancer patients. RESULTS: Through analyses of several independent breast cancer cohorts, we found the correlation of the LAPTM4B and p27kip1 expression. Remarkably, the knockdown of LAPTM4B restored p27kip1 expression and inhibited the aggressiveness of breast cancer cells. Meanwhile, the knockdown of p27kip1 relieved the suppression of cell migration. Consistent with the analyses of human breast cancer cohorts, the immunohistochemistry results showed that the expression levels of LAPTM4B and p27kip1 were correlated in 188 triple-negative breast cancer samples (p= 0.019). We also validated that the higher LAPTM4B expression, the lower p27kip1 expression (p= 0.0001), and the LAPTM4B+/p27kip1- subgroup (p< 0.0001) were poor prognostic indicators, as well as the higher histologic grade (p= 0.0001). In the multivariate Cox regression, p27kip1 expression was considered as an independent predictor of survival (p< 0.001). CONCLUSIONS: The overexpression of LAPTM4B and the loss of p27kip1 expression are correlated. Meanwhile, the up-regulated expression of LAPTM4B together with the down-regulated expression of p27kip1 could classified a group of breast cancer patients with poor prognosis, consequently considered as a potentially prognostic marker and candidate target for therapeutic intervention of triple-negative breast cancer.

Exceptionally high UBE2C expression is a unique phenomenon in basal-like type breast cancer and is regulated by BRCA1.

Ubiquitin-conjugating enzyme 2C (UBE2C) is overexpressed in various types of cancer, leading to poor outcomes and drug resistance. UBE2C may also have a critical role in phenotypes associated with poor prognosis in breast cancer; however, the relationship between UBE2C expression and clinical outcome in breast cancer subtypes has not previously been investigated. We firstly analyzed breast cancer patient data and immunohistochemistry of breast cancer patient samples. We demonstrated that UBE2C was associated with poor prognosis in breast cancer, particularly basal-like breast cancer, a subtype with aggressive clinical features. Interestingly, we found that there was a close relationship between the expression of BRCA1 and UBE2C in the MCF-7 and MDA-MB-231 breast cancer cell lines. Upregulation of BRCA1 could inhibit the expression of UBE2C. In cells with BRCA1 silenced down, expression of UBE2C was obviously increased, with a concurrent decrease in cellular sensitivity to doxorubicin. Suppression of UBE2C expression by RNA interference led to decrease the mRNA expressions of BCRP, MRP1 and P-gp in doxorubicin-treated MDA-MB-231 cells. Moreover, treatment with 1µg/ml doxorubicin led to increased expression of UBE2C. The results show high expression of UBE2C is a potential prognostic factor of poor outcome in basal-like breast cancer. Moreover, loss of BRCA1 function results in an increase in UBE2C expression and chemical resistance to doxorubicin in breast cancer cells.