Aug 26, 20 hmga2 also induces sdc2 through a mir200independent mechanism, promoting breast tumor growth, survival and metastasis in mouse xenografts. In addition, in a mouse allograft model, hmga2 overexpression converted nonmetastatic 4to7 breast cancer cells to metastatic cells that homed specifically to liver. Hmga2 regulates lung cancer proliferation and metastasis. Lung cancer is the leading cause of cancer death in both men and women in the united states, accounting for approximately 30% of cancer. Signaling via the phosphoinositide 3kinase pi3k pathway, rasmitogenactivated protein kinase mapk and oxidative stress has been implicated in vigorous activation of the hmga2. Cancer stem cells cscs have been defined as a small subset of cancer cells within the tumor bulk that show potential causes of malignant properties of tumors, such as tumor initiation, metastasis, recurrence, and chemoresistance. Tumor repopulation is a major cause of radiotherapy failure. Lncrna hotair influences cell growth, migration, invasion. The transcription factor nrf2 is the master regulator of the cellular antioxidant response. Most cancer deaths are due to cancer that has metastasized. Overexpression of hmga2 promotes tongue cancer metastasis.
Frontiers the lin28let7 pathway in cancer genetics. Both tet1 and hoxa9 suppress breast tumor growth and metastasis in mouse xenografts. Here, we demonstrate that trop2 is significantly elevated in crpc and nepc and represents a driver of metastatic nepc. Cancers free fulltext an integrated bioinformatics. To test this, we quantified parylation in our tumor cell models with increasing concentrations of olaparib. Interestingly, we also found that the bone metastasis seeding of tumor cells were greatly enhanced when hmga2 was overexpressed figure 2f. Rkip and hmga2 regulate breast tumor survival and metastasis.
Hmga2, a driver of inflammation, is associated with. This protein mesh is known as the extracellular matrix. H19 promotes pancreatic cancer metastasis by derepressing. Metastasis of tumor cells is enhanced by downregulation of bit1. For tumors to progress efficiently, cancer cells must overcome barriers of oxidative stress. Stc2 overexpression mediated by hmga2 is a biomarker for. Full text hmga2 is associated with epithelialmesenchymal. And we proposed that hmga2 may serve as an important contributor to chemoresistance to doxorubicin through stimulating p53 ser15 phosphorylation in breast cancer cells. The nonhistone chromatinbinding protein hmga2 is expressed predominantly in the mesenchyme before its differentiation, but it is also expressed in tumors of epithelial origin. May 30, 20 however, little is known regarding in vivo modulation of hmga2 and its effector functions in tumor metastasis.
Amplification of hsamir191425 locus promotes breast cancer proliferation and metastasis by targeting dicer1. We performed a metaanalysis to determine the clinicpathological and prognostic value of hmga2 overexpression in different human tumors. These findings implicate a role of bit1 in metastasis. The newly pathological sites, then, are metastases mets. Let7a suppresses glioma cell proliferation and invasion. Metastatic cells can migrate from a primary tumor to distant organs through two routes. Hmga2tet1hoxa9 signaling pathway regulates breast cancer. Morishita a 1, zaidi mr, mitoro a, sankarasharma d, szabolcs m, okada y, darmiento j, chada k.
Metastasis to long distance organs is the main reason leading to morality of tongue squamous cell. Rna cancer tissue category is calculated based on mrna expression levels across all 17 cancer tissues and include. Together, these results suggest that hmga2 is a direct target of mir1855p. Hmga2, a member of hmga family that have the athook dnabinding motif, plays an essential role in cell transformation, cancer progression and intimate with neoplastic malignancies thanos et al. Uterine intravenous leiomyomatosis with an isolated large. Hmga2 is a driver of tumor metastasis semantic scholar. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the nrf2 pathway as a driver of cancer progression, metastasis. Actinlike 6a actl6a is vital for embryogenesis and differentiation and is also critical for metastasis. The genes comprising the hmga2 tet1hoxa9 pathway are coordinately regulated in breast cancer. Metastasis is a pathogenic agents spread from an initial or primary site to a different or secondary site within the hosts body. In this study, we showed that ectopic expression of hmga2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo in contrast, the silencing of hmga2 produced the opposite effects in vitro and in vivo chromatin immunoprecipitationpcr and luciferase assays revealed that hmga2 bound. Epithelial mesenchymal transition emt plays an important role in invasion and metastasis. Overexpression of hmga2 is correlated with a higher risk of metastasis and an unfavorable prognosis in patients with cancer. Except let7, other tumor suppressor mirnas, such as mir4903p, mir33a, mir33b, mir154, and mir204, directly target hmga2 3utr and reduce its effects on promoting.
In this study, we found that not only the levels of h19 was overexpressed in pdac compared with adjacent normal tissues, but also h19 expression was upregulated remarkably in primary tumors. This attachment between the cells and the extracellular matrix is particularly. Although both genes are regulated by hmga2, the specific functions of lox and sdc2 are likely to be different as each of them appears to play a key role in breast cancer progression. Ectopic expression of hmga2 in epithelial cells induces epithelialmesenchymal transition emt, which has been implicated in the acquisition of metastatic characters in tumor cells. The transcriptional modulator hmga2 promotes stemness and. Antigenspecific t cell responses are critical for tumor clearance baitsch et al. Overexpression of hmga2 in bladder cancer and its association with clinicopathologic features and prognosis hmga2 as a prognostic marker of bladder cancer. Since increased hmga2 expression in hsrgbm1 does not lead to enhanced proliferation. As1 promotes glioma progression by regulating mir 185 5p. Lncrna expressions a and hmga2 b in glioma tissues were examined by qrt. The long noncoding rna lncrna h19 has been recently characterized as an oncogenic lncrna in some tumors. Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis.
Transcriptional activation of fn1 and il11 by hmga2 promotes. The genes comprising the hmga2 tet1hoxa9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. Jul 01, 2016 in our study, ectopic expression of hmga2 significantly enhanced the expression of phosphop53 ser15 in breast cancer cells following doxorubicin treatment. A wealth of genomic and transcriptional data for tumors. Hmga2 is a driver of tumor metastasis new jersey research. High mobility group athook 2 hmga2 is highly expressed in multiple metastatic carcinomas, in which it contributes to cancer progression, metastasis and poor prognosis by upregulating snail expression and inducing epithelial. Hmga2 as a functional antagonist of parp1 inhibitors in. The microrna let7 is largely responsible for the expression of hmga2 in malignant tumor formation shell et al.
Transcriptional activation of fn1 and il11 by hmga2. Mar 25, 2014 the two main reasons for death of cancer patients, tumor recurrence and metastasis, are multistage cellular processes that involve increased cell plasticity and coincide with elevated resistance to anticancer treatments. Here the authors report that an n6methyladenosine modified circular rna is upregulated in colorectal cancer and promotes liver metastasis by enhancing the stability of hmga2. N2 highgrade serous cancer hgsc is a lethal form of ovarian cancer due to invasion and early metastasis. Hmga2 is a driver of tumor metastasis researchgate. They can enter the bloodstream directly, or they can enter a lymph node adjacent to the primary tumor. Here we report that hmga2 loss of function in a mouse model of cancer reduces tumor. The metastatic program comprises multiple steps including early events such as tumor cell migration, invasion and intravasation.
Aberrant overexpression of high mobility group athook 2 hmga2 is frequently found in cancers and hmga2 has been considered an anticancer therapeutic target. Rii, which also localized to the invasive front of tumors. To begin the process of metastasis, a malignant cell must first break away from the cancerous tumor. Glioma tumor xenograft models on mice were built to evaluate the effects of let7a and hmga2 sirna on glioma tumors in vivo. Oxidized lowdensity lipoprotein receptor 1 olr1, a lectinlike scavenger receptor that recognizes several ligands, such as oxidized lowdensity lipoprotein, was previously reported in cardiovascular and. Hmga2 regulates transcription of the imp2 gene via an intronic regulatory element in cooperation with nuclear factorkappab. Epithelialtomesenchymal transition emt is a key contributor to metastasis in many cancer types, including thyroid cancer and is known to confer stem celllike properties. Overexpression of mir194 reverses hmga2driven signatures. High mobility group athook 2 hmga2 is highly expressed in multiple metastatic carcinomas, in which it contributes to cancer progression, metastasis. Although dietary antioxidant supplementation or activation of endogenous antioxidants by nrf2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis. Little is known about the biological mechanisms that allow tumor cells to survive and grow within lymph nodes.
Hmga2 and smads coregulate snail1 expression during induction of epithelialtomesenchymal transition. Raza zaidi 3, akira mitoro, devipriya sankarasharma, matthias szabolcs 2, yasunori okada 4, jeanine darmiento 1, and kiran chada 3. Metabolic competition in the tumor microenvironment is a. Bach1 stabilization by antioxidants stimulates lung cancer. Previous investigations highlighted that dying tumor cells played vital roles in tumor repopulation through promoting proliferation of the residual tumor. Hmga2 as a functional antagonist of parp1 inhibitors in tumor. Thuault s, tan ej, peinado h, cano a, heldin ch, moustakas a. Overexpression of mir194 reverses hmga2driven signatures in. Ectopic expression of hmga2 in epithelial cells induces epithelialmesenchymal transition emt, which has been implicated in the acquisition of metastatic characters in tumor. The immunofluorescence studies demonstrated that hmga2 significantly enhanced the expression of the mesenchymal. Cellbased highthroughput compound screening reveals.
The metastatic program comprises multiple steps including early events such as tumor cell migration, invasion and intravasation into vessels and later events leading to growth and colonization at distant organ sites 1. It has been confirmed that hmga2 is a direct target of tumor suppressor mirna let7, and deregulation of let7 inhibition on hmga2 contributes to tumorigenesis and metastasis. Among all tumor suppressor micrornas, reduced let7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Morishita a, zaidi mr, mitoro a, sankarasharma d, szabolcs m, okada y, darmiento j and chada k. Hmga2 positive cells were identified at the invasive front of human and mouse tumors. Nepc is a highly aggressive subtype of prostate cancer that is increasing in incidence, likely due to use of new secondary androgen deprivation therapies. Elevated hmga2 expression is associated with cancer. Trop2 is a driver of metastatic prostate cancer with. Gain of epithelialmesenchymal transition emt contributes to the aggressiveness of hgsc. Trop2 overexpression increases tumor growth, drives metastasis. Trop2 overexpression increases tumor growth, drives metastasis and neuroendocrine phenotype, and significantly increases. Our findings establish trop2 as a driver and therapeutic target for metastatic prostate cancer. Raza zaidi2, akira mitoro2, devipriya sankarasharma2, matthias szabolcs3, yasunori okada4, jeanine darmiento1, kiran.
Metastasis is the key process that leads to death from solid tumors. Metastasis to long distance organs is the main reason leading to morality of tongue squamous cell carcinoma tscc. Lncrna hotair affected cell growth, metastasis, and apoptosis via the mir. Bc cells progression was mediated by lncrna hotair via affecting mir. Jul 15, 20 however, little is known regarding in vivo modulation of hmga2 and its effector functions in tumor metastasis. Oct 16, 2019 a, b decreased tumor metastasis formed in the livers of mice through the inferior hemispleen implantation of circnsun2konckdown tc71 pdx cells was rescued by overexpression of hmga2. Here the authors report that an n6methyladenosine modified circular rna is upregulated in colorectal cancer and promotes liver metastasis by enhancing the stability of hmga2 mrna. Hmga2 is a driver of tumor metastasis cancer research. Results expression of bit1 is reduced in invasive breast tumors since anoikis resistance is a determinant of tumor progression and metastasis in tumor cells, we tested the possibility that the bit1. However, the role of h19 in pancreatic ductal adenocarcinoma pdac remains unclear. Dying tumor cellderived exosomal mir1945p potentiates. The expression level of let7a significantly downregulated in glioma tissues, while the hmga2. To investigate whether the effects of mir4855p on cell metastasis and etm are related to hmga2, the t24 cells overexpressing mir4855p were transfected with hmga2 pcdna3. Ttest results are shown for expression in tumors vs.
Normal distribution across the dataset is visualized with box plots, shown as median and 25th and 75th percentiles. Expression of hmga2 in cancer summary the human protein atlas. Inverse relationships for let7 and target mrnas could be discerned by plotting mirnaseq data against mrnaseq data for let7c vs. It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer. Regional chromosomal alterations of variable frequencies were also observed in ivl, showing overlaps with uterine leiomyosarcoma 12. Indeed, many hallmarks of cancer define that the malignant phenotype of tumor cells are controlled by lncrnas. Moreover, exosomesdepleted cm of irradiated cells lost the inhibitory effects fig. Let7 represses carcinogenesis and a stem cell phenotype.
Overexpression of hmga2 promotes tongue cancer metastasis through emt pathway xiao. In this study, a pan cancer genomics survey based on cancer cell line encyclopedia ccle and the cancer genome atlas tcga data indicated that hmga2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Aug 26, 20 metastasis is the key process that leads to death from solid tumors. Here we report that hmga2 loss of function in a mouse model of cancer reduces tumor multiplicity. In this study, we showed that ectopic expression of hmga2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo. Hmga2 expression is associated with cellular transformation berlingieri et al.
Interestingly, expression of hmga2 enhanced tgfb signaling by activating expression of the tgf. In normal tissue, cells adhere both to one another and to a mesh of protein filling the space between them. Metastasis is common in the late stages of cancer and it can occur via the blood or the lymphatic system or both. Together our results argued that hmga2 plays a critical role in emt by activating the tgf.
Circulating levels of the mirnas, mir194, and mir29b, as clinically useful biomarkers for colorectal cancer. However, the underlying molecular mechanism of its overexpression is still elusive. Accordingly, abundant expression of hmga2 is correlated with metastasis and poor survival in colon cancer patients wang et al. The dispersed tumors are called metastatic tumors, while the original is called the primary tumor.
Furthermore, hmga2 reexpression is causally linked to cell transformation, epithelialmesenchymal transition and metastasis, also in the context of cancer stem cells 68. In contrast, the silencing of hmga2 produced the opposite effects in vitro and in vivo. Olr1 promotes pancreatic cancer metastasis via increased c. Hmga2 is a driver of tumor metastasis keio university. Hmga2 is a driver of tumor metastasis asahiro morishita1, m. Therefore, although both wildtype and truncated hmga2 may promote prostate tumor progression, wildtype hmga2 acts by inducing emt via mapk pathway. Activation of either lin28a or lin28b, two highly related rna binding proteins rbps and protooncogenes, is responsible for the global posttranscriptional downregulation of the let7 microrna family observed in many cancers. Hmga2 is a driver of tumor metastasis asahiro morishita 1, m.