C/EBP beta-LIP induces cancer-type metabolic reprogramming by regulating the let-7/LIN28B circuit in mice

The transcription factors LAP1, LAP2 and LIP are derived from the Cebpb-mRNA through the use of alternative start codons. High LIP expression has been associated with human cancer and increased cancer incidence in mice. However, how LIP contributes to cellular transformation is poorly understood. Here we present that LIP induces aerobic glycolysis and mitochondrial respiration reminiscent of cancer metabolism. We show that LIP-induced metabolic programming is dependent on the RNA-binding protein LIN28B, a translational regulator of glycolytic and mitochondrial enzymes with known oncogenic function. LIP activates LIN28B through repression of the let-7 microRNA family that targets the Lin28b-mRNA. Transgenic mice overexpressing LIP have reduced levels of let-7 and increased LIN28B expression, which is associated with metabolic reprogramming as shown in primary bone marrow cells, and with hyperplasia in the skin. This study establishes LIP as an inducer of cancer-type metabolic reprogramming and as a regulator of the let-7/LIN28B regulatory circuit

Functions of the C/EBPβ isoforms in breast cancer

Breast cancer is the most commonly diagnosed type of cancer in women and the survival outcome is strongly dependent on the stage of breast cancer at diagnosis. Therefore, it is essential to identify oncogenic factors that contribute to breast cancer development and metastasis. The transcription factor C/EBPβ is known to regulate cell proliferation and differentiation in a variety of tissues. The transactivation capacity of C/EBPβ is largely determined by the ratio between the isoforms C/EBPβ-LAP and C/EBPβ-LIP. Previous studies have shown that C/EBPβ-LIP-depleted mice display improved metabolic health, a prolonged lifespan, and reduced cancer incidence. Other studies have found high expression of LIP in grade III, Estrogen receptor (ER) and Progesterone (PR) receptor negative human breast cancer and have linked high LIP expression with increased mammary epithelial proliferation. We find that cell lines derived from triple-negative breast cancer (TNBC, lacking the Estrogen and Progesterone receptors and HER2 expression) have a very high LIP/LAP ratio. Reducing the LIP/LAP ratio by exogenous expression of LAP in TNBC cell lines reduces migration and invasion of the breast cancer cells. Moreover, the overexpression of LIP promotes cell migration of untransformed mammary epithelial cells. Transcriptomics data obtained from TNBC cells with CEBPB knockout show a regulation of migration and extracellular matrix-related genes. Our data propose a role for the LIP/LAP ratio in the regulation of breast cancer cell migration and ECM remodelling, two key characteristics that are associated with the aggressive phenotype of TNBC cells

Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling

Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer cells and tumors. Consequently, Lip-FLLL32 suppressed pancreatic cancer cell growth, and exhibited synergetic effects with gemcitabine and radiation treatment in vitro and in vivo. Furthermore, Lip-FLLL32 reduced ALDH1-positive CSC population and modulated several potential stem cell markers. These results demonstrate that Lip-FLLL32 suppresses pancreatic tumor growth and sensitizes pancreatic cancer cells to radiotherapy through inhibition of CSCs in a STAT3-dependent manner. By targeting pancreatic CSCs, Lip-FLLL32 provides a novel strategy for pancreatic cancer therapy via overcoming radioresistance

Filipinos’ Interest in Oral Cancer

Objective: This study analyzed the health-seeking behavior of Filipinos through relative search volume in Google Trends using oral cancer, mouth cancer, tongue cancer, gum cancer, and lip cancer as predetermined search terms. Methods: Comma-separated values files containing relative search volumes of search trends pertaining to oral cancer from 2009 to 2019 were assessed. Brown-Forsythe one-way ANOVA was used to measure differences of oral cancer between years and among months. Repeated measures two-way ANOVA measured differences among the searches for mouth cancer, tongue cancer, gum cancer, and lip cancer through the years. Time series models were fitted and used to forecast search interests. Results: The results revealed that interests in oral cancer were significantly higher in 2019 (43.75±5.5, p<0.05) compared to 2009 (29.0 ± 6.7). In terms of months, searches were higher in February (45.0 ± 6.6) compared to May (24.8 ± 3.4, p=0.015), June (25.3 ± 4.4, p=0.020), and December (26.5 ± 4.0, p=0.038). Search interests for gum cancer and lip cancer remained significantly lower from 2011 to 2019, and tongue cancer from 2016 to 2018 but approximated mouth cancer in 2019. The forecast shows mouth cancer (31.67%), tongue cancer (23.75%), and lip cancer (3.83%) fluctuating through the year, while gum cancer (8%) will remain steady in 2020. Conclusion: Health-seeking behavior through search trends show an increased interest in oral cancer in 2019 and during February. Search interests will fluctuate in 2020, but at the end of the year will decrease for mouth cancer and tongue cancer, will increase for lip cancer, and will remain steady for gum cancer

Mortality rate of lip, oral cavity and pharynx malignant tumors in Serbia within a period 1991-2009

Background/Aim. Lip, oral cavity and pharynx malignant tumors account for 3.7% of all cancer deaths worldwide, with significant geographic variations in frequency and distribution. The aim of this descriptive epidemiologic study was to analyze the mortality rate of lip, oral cavity and pharynx malignant tumors in Serbia proper within a period 1991-2009. Methods. Mortality rates standardized directly using the world population as the standard were used in data analysis. Linear trend and regression analyses were used to analyze rate trends in mortality. Results. The Serbian population demonstrated an increase in the mortality of lip, oral cavity and pharynx malignant tumors (y = 3.32 + 0.03×; p = 0.002; average annual percent change = + 0.8). The male population showed a significant increase in mortality trend (y = 5.90 + 0.03×; p = 0.020; % change = + 0.9), while the female population did not show a significant increase in mortality. The male/female cancer mortality ratio was 5.5:1. Mortality rates for lip, oral cavity and pharynx cancer increased with age in both genders, with rates being the highest in the population aged 85 and older. Increasing trends of lip, oral cavity and pharynx cancer mortality were observed in males aged 50-54; the average annual percent change was + 7.4 % (95% CI, 6.2-9.0). The population of both genders aged 55-59 demonstrated an increase in lip, oral cavity and pharynx cancer mortality, the increase being + 1.8% (95% CI, 1.4-2.2) in men and + 34.3% (95% CI, 28.4-40.2) in women. Conclusion. The increasing trend in lip, oral cavity and pharynx cancer mortality points to the necessity to investigate etiology and improve primary and secondary prevention measures

Effect of COVID-19 on Oral Cancer Search

Objective: Oral cancer is one of the most common malignancies in developing countries, but studies using global data are scarce. The aim of this study is to analyze the search interests for oral cancer using mouth cancer, tongue cancer, gum cancer, and lip cancer as common keywords. Methods: Internet searches relating to oral cancer from 2010 to 2020, from 250 countries and dependent areas, were retrieved from Google Trends. Color densities in a heat map were used to show geographic differences. Kruskal-Wallis test with post hoc Dunn’s analysis was used to perform yearly comparisons of searches for mouth cancer, tongue cancer, gum cancer, and lip cancer. Search results within 2020 were also compared to determine differences. Forecasting searches from 2021 to 2022 were done by fitting time series models. Results: From 29 of 250 (11.6%) countries, the highest search values were observed for mouth cancer in Sri Lanka, Qatar, Bangladesh, Finland, Netherlands, Spain, and France. Compared to 2020, greater searches were seen in 2018 (Mdn = 91%, P = 0.023) and 2019 (Mdn = 94%, P = 0.012) for mouth cancer, and 2019 (Mdn = 17%, P = 0.035) for lip cancer. The relative search volumes for gum cancer and lip cancer were substantially lower than mouth cancer during the COVID-19 pandemic. Conclusion: Higher-income countries tend to be more interested in seeking information about oral cancer. Noteworthy decline in the interest in seeking information online for oral cancer may have crucial implications during the COVID-19 pandemic. Google Trends offer an invaluable and inexpensive means for oral cancer surveillance and health-seeking behavior

Smooth-car mixed models for spatial count data

Penalized splines (P-splines) and individual random effects are used for the analysis of spatial count data. P-splines are represented as mixed models to give a unified approach to the model estimation procedure. First, a model where the spatial variation is modelled by a two-dimensional P-spline at the centroids of the areas or regions is considered. In addition, individual area-effects are incorporated as random effects to account for individual variation among regions. Finally, the model is extended by considering a conditional autoregressive (CAR) structure for the random effects, these are the so called “Smooth-CAR” models, with the aim of separating the large-scale geographical trend, and local spatial correlation. The methodology proposed is applied to the analysis of lip cancer incidence rates in Scotland.Mixed models, P-splines, Overdispersion, Negative Binomial, PQL, CAR models, Scottish lip cancer data

Clinico-epidemiological profile and treatment outcome of lip cancer: a retrospective study from north India

Background: Aim of present study to evaluate the Clinico-epidemiological profile and treatment outcome of Lip Cancer. Methods: This was a retrospective study performed in our hospital. All necessary clinical and epidemiological details of the 11 cases diagnosed with lip cancer from January 2016 to December 2021 were analysed. Results: The total number of new malignant cases diagnosed as lip cancer between January 2016 and December 2021 were 11, which comprised 6 male (55%) and 5 (45%) female. The male-to-female ratio was (1.2:1). The most common histological type was SCC, i.e., in 9 (81.8%) of the total number of cases and BCC was in 2 patients (18.2%). Overall survival at 5 years was 89% in our study. Conclusions: In conclusion, we have reported higher levels of lip cancer among men and those above 45 years of age. The important prognostic factors for overall survival in these patients were cancer stages. Better survival is achieved with surgery alone in the early stages and with adjuvant radiotherapy in the later stages

Evaluation of clinical effectiveness of paclitaxel and ursolic acid co-loaded liposomes as enhanced treatment for head and neck squamous cell carcinoma

Purpose: To enhance the clinical effectiveness of paclitaxel (PTX) by co-delivery with ursolic acid (UA) for the treatment of head and neck cancer.Methods: Co-loaded liposomes of PTX and UA (UA-PTX-LiP) were prepared by thin-film hydration method. Their size and loading efficiency were determined using dynamic light scattering (DLS) technique and high performance liquid chromatography (HPLC), respectively. The effectiveness of UAPTX-LiP against HSC-3 human head and neck cancer cell-lines was compared with that of PTX liposome (PTX-LiP) using systemic cell-based in vitro evaluation with MTT assay. Fluorescent microscopy was used for cell uptake studies.Results: The size of the prepared UA-PTX-LiP was 126.5 ± 3.22 nm. The ratiometric system for PTX and UA as liposom es revealed significantly enhanced cytotoxicity, with comparatively lower IC50, whencompared to individual PTX-Lip. Fluorescent microscopy revealed the internalization ability of UA-PTXLiP by targeted delivery of PTX in HSC-3 human head and neck cancer cell-line.Conclusion: These results show that UA-PTX-LiP successfully enhances the therapeutic potential and clinical outcomes of PTX in head-and-neck cancer, and also demonstrate the useful effect of combination of UA and PTX in chemotherapy.Keywords: Paclitaxel, Ursolic acid, Combination chemotherapy, Head-and-neck squamous cance