Abstract:Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independ… Show more
“…We found that treatment with an Erk inhibitor, SCH772984, significantly reduced phosphorylation of the Erk substrate Rsk and noticeably upregulated Irf6 in MCF-ErbB2 cells in 3D culture (Fig. 5 a) [ 37 , 38 ]. Fig.…”
BackgroundThe ability of solid tumor cells to resist anoikis, apoptosis triggered by cell detachment from the extracellular matrix (ECM), is thought to be critical for 3D tumor growth. ErbB2/Her2 oncoprotein is often overproduced by breast tumor cells and blocks their anoikis by partially understood mechanisms. In our effort to understand them better, we observed that detachment of nonmalignant human breast epithelial cells from the ECM upregulates the transcription factor Irf6. Irf6 is thought to play an important role in mammary gland homeostasis and causes apoptosis by unknown mechanisms. We noticed that ErbB2, when overproduced by detached breast epithelial cells, downregulates Irf6.MethodsTo test whether ErbB2 downregulates Irf6 in human ErbB2-positive breast cancer cells, we examined the effect of ErbB2 inhibitors, such as the anti-ErbB2 antibody trastuzumab or the ErbB2/epidermal growth factor receptor small-molecule inhibitor lapatinib, on Irf6 in these cells. Moreover, we performed Irf6 IHC analysis of tumor samples derived from the locally advanced ErbB2-positive breast cancers before and after neoadjuvant trastuzumab-based therapies. To examine the role of Irf6 in anoikis of nonmalignant and ErbB2-overproducing breast epithelial cells, we studied anoikis after knocking down Irf6 in the former cells by RNA interference and after overproducing Irf6 in the latter cells. To examine the mechanisms by which cell detachment and ErbB2 control Irf6 expression in breast epithelial cells, we tested the effects of genetic and pharmacological inhibitors of the known ErbB2-dependent signaling pathways on Irf6 in these cells.ResultsWe observed that trastuzumab and lapatinib upregulate Irf6 in ErbB2-positive human breast tumor cells and that neoadjuvant trastuzumab-based therapies tend to upregulate Irf6 in human breast tumors. We found that detachment-induced Irf6 upregulation in nonmalignant breast epithelial cells requires the presence of the transcription factor ∆Np63α and that Irf6 mediates their anoikis. We showed that ErbB2 blocks Irf6 upregulation in ErbB2-overproducing cells by activating the mitogen-activated protein kinases that inhibit ∆Np63α-dependent signals required for Irf6 upregulation. Finally, we demonstrated that ErbB2-driven Irf6 downregulation in ErbB2-overproducing breast epithelial cells blocks their anoikis and promotes their anchorage-independent growth.ConclusionsWe have demonstrated that ErbB2 blocks anoikis of breast epithelial cells by downregulating Irf6.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1080-1) contains supplementary material, which is available to authorized users.
“…We found that treatment with an Erk inhibitor, SCH772984, significantly reduced phosphorylation of the Erk substrate Rsk and noticeably upregulated Irf6 in MCF-ErbB2 cells in 3D culture (Fig. 5 a) [ 37 , 38 ]. Fig.…”
BackgroundThe ability of solid tumor cells to resist anoikis, apoptosis triggered by cell detachment from the extracellular matrix (ECM), is thought to be critical for 3D tumor growth. ErbB2/Her2 oncoprotein is often overproduced by breast tumor cells and blocks their anoikis by partially understood mechanisms. In our effort to understand them better, we observed that detachment of nonmalignant human breast epithelial cells from the ECM upregulates the transcription factor Irf6. Irf6 is thought to play an important role in mammary gland homeostasis and causes apoptosis by unknown mechanisms. We noticed that ErbB2, when overproduced by detached breast epithelial cells, downregulates Irf6.MethodsTo test whether ErbB2 downregulates Irf6 in human ErbB2-positive breast cancer cells, we examined the effect of ErbB2 inhibitors, such as the anti-ErbB2 antibody trastuzumab or the ErbB2/epidermal growth factor receptor small-molecule inhibitor lapatinib, on Irf6 in these cells. Moreover, we performed Irf6 IHC analysis of tumor samples derived from the locally advanced ErbB2-positive breast cancers before and after neoadjuvant trastuzumab-based therapies. To examine the role of Irf6 in anoikis of nonmalignant and ErbB2-overproducing breast epithelial cells, we studied anoikis after knocking down Irf6 in the former cells by RNA interference and after overproducing Irf6 in the latter cells. To examine the mechanisms by which cell detachment and ErbB2 control Irf6 expression in breast epithelial cells, we tested the effects of genetic and pharmacological inhibitors of the known ErbB2-dependent signaling pathways on Irf6 in these cells.ResultsWe observed that trastuzumab and lapatinib upregulate Irf6 in ErbB2-positive human breast tumor cells and that neoadjuvant trastuzumab-based therapies tend to upregulate Irf6 in human breast tumors. We found that detachment-induced Irf6 upregulation in nonmalignant breast epithelial cells requires the presence of the transcription factor ∆Np63α and that Irf6 mediates their anoikis. We showed that ErbB2 blocks Irf6 upregulation in ErbB2-overproducing cells by activating the mitogen-activated protein kinases that inhibit ∆Np63α-dependent signals required for Irf6 upregulation. Finally, we demonstrated that ErbB2-driven Irf6 downregulation in ErbB2-overproducing breast epithelial cells blocks their anoikis and promotes their anchorage-independent growth.ConclusionsWe have demonstrated that ErbB2 blocks anoikis of breast epithelial cells by downregulating Irf6.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1080-1) contains supplementary material, which is available to authorized users.
“…ATG12 regulates the apoptotic pathway by binding and inactivating BCL2 and MCL1 [53] whereas STEAP4 is a metalloreductase, involved in responses to nutrients, inflammatory and oxidative stress, fatty acid metabolism, and glucose metabolism [54–56]. Recently, it has been found that ATG12 and STEAP4 were down- and up-regulated respectively in human CRC and predicted poor prognosis [57, 58]. Again, the dysregulation of CEP55 , CLDN4 , CHAF1A , H19 and STEAP4 have been found to significantly correlate with CRC tumor stage, aggressiveness, metastasis and poor prognosis [59–63].…”
Background
Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate.
Methods
Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of
SMC1A
overexpression and mutated
SMC1A
were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq.
Results
Here we showed that
SMC1A
cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation.
Conclusion
Collectively, these results support a role of defective cohesin in the development of human colorectal cancer.
Electronic supplementary material
The online version of this article (10.1186/s13046-019-1116-0) contains supplementary material, which is available to authorized users.
“…In 2018, Yoo et al transfected rat intestinal epithelial cells with oncogenic H-RAS and observed that Atg12 was downregulated in these cells due to increased proteasomal degradation, mediated by MAPK activation. In addition, this same group demonstrated that ectopic expression of Atg12 in oncogenic-RAS intestinal epithelial cells resulted in decreased clonogenicity and increased cell death by apoptosis ( 35 ). Although increased expression of Atg12 has been found in certain solid tumors, in the early stages of carcinogenesis it might participate in the induction of autophagy also in activation of apoptosis.…”
Section: Autophagy and Apoptosis Crosstalk In Cancermentioning
During tumorigenesis, cancer cells are exposed to a wide variety of intrinsic and extrinsic stresses that challenge homeostasis and growth. Cancer cells display activation of distinct mechanisms for adaptation and growth even in the presence of stress. Autophagy is a catabolic mechanism that aides in the degradation of damaged intracellular material and metabolite recycling. This activity helps meet metabolic needs during nutrient deprivation, genotoxic stress, growth factor withdrawal and hypoxia. However, autophagy plays a paradoxical role in tumorigenesis, depending on the stage of tumor development. Early in tumorigenesis, autophagy is a tumor suppressor via degradation of potentially oncogenic molecules. However, in advanced stages, autophagy promotes the survival of tumor cells by ameliorating stress in the microenvironment. These roles of autophagy are intricate due to their interconnection with other distinct cellular pathways. In this review, we present a broad view of the participation of autophagy in distinct phases of tumor development. Moreover, autophagy participation in important cellular processes such as cell death, metabolic reprogramming, metastasis, immune evasion and treatment resistance that all contribute to tumor development, is reviewed. Finally, the contribution of the hypoxic and nutrient deficient tumor microenvironment in regulation of autophagy and these hallmarks for the development of more aggressive tumors is discussed.
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