FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention

Entrepreneurial intention among University students in Malaysia: integrating self-determination theory and the theory of planned behavior

The present study endeavors to develop a deeper understanding of the motivational processes involved in intentional entrepreneurial behavior. For this purpose, it integrates the social cognitive approach of the theory of planned behavior (TPB) and the organismic theory of motivation of self-determination theory (SDT). More specifically, it tests the role of basic psychological needs of autonomy, competence and relatedness as defined in SDT in shaping university students’ attitudes and intentions toward entrepreneurship. The sample of this study consisted of 438 (Males = 166, Females =272) 3rd and4th year university students from four Malaysian Public Universities. The results of the study show that the model strongly explains about 71% of the variance in entrepreneurial intention. Basic psychological needs of autonomy, competence and relatedness have a strong indirect impact on entrepreneurial intention via their attitudinal antecedents: attitude,subjective norm, and perceived behavioral control. This indicates a full-mediational model,where the attitudinal factors operated as transmitters of effects from the distal constructs ofSDT on entrepreneurial intention. These findings confirm that both SDT and the TPB provide complementary explanations of the motivational processes of entrepreneurial behavior. The study contributes to the existing knowledge by providing a theory-based understanding of the role of motivations in the formation of entrepreneurial intentions. It opens the way for future research to analyze how alternative motivations may affect new venture creation, survival and success

Entrepreneurial orientation and the performance of service business

Entrepreneurial orientation, Entrepreneurship, Service business, Performance, Culture, Japanese restaurant,

FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. Methods: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. Results: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. Conclusions: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. Lay summary: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found that the microRNA (miRNA) cluster including miR181ab1 is a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically engineered mouse models of Kras-driven lung and pancreatic cancer was deleterious to tumor initiation and progression. Expression of both resident miRNAs in the Mir181ab1 cluster, miR181a1 and miR181b1, was necessary to rescue the Mir181ab1-loss phenotype, underscoring their nonredundant role. In human cancer cells, depletion of miR181ab1 impaired proliferation and 3D growth, whereas overexpression provided a proliferative advantage. Lastly, we unveiled miR181ab1-regulated genes responsible for this phenotype. These studies identified what we believe to be a previously unknown role for miR181ab1 as a potential therapeutic target in 2 highly aggressive and difficult to treat KRAS-mutated cancers