Hmga2 translocation induced in skin tumorigenesis

Li, Yong; Pi, X.; Boland, Kelsey; Lad, Sonali; Johnson, Krista; Verfaillie, Catherine M.; Morris, Rebecca

doi:10.18632/oncotarget.16272

Cited by 7 publications

(7 citation statements)

References 32 publications

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“…In patient tissue, we found an increase in HMGA2 expression along with translocation into the nucleus with prostate cancer progression while in normal prostate tissue, there was low HMGA2 expression expressed at the cell membrane. This is similar to a study by Li et al, which found HMGA2 translocated from the membrane into the nucleus in a high passage of keratinocytes (passage 14) and during carcinoma development [30]. In our study, lower grade prostate cancer tissues showed cytoplasmic expression of HMGA2 along with positive expression in stroma.…”

Section: Discussionsupporting

confidence: 92%

High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer

Hawsawi

Henderson

Burton

et al. 2018

Biochemical and Biophysical Research Communications

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Studies have shown that High mobility group A2 (HMGA2), a non-histone protein, can promote epithelial-mesenchymal transition (EMT), which plays a critical role in prostate cancer progression and metastasis. Interestingly, full-length or wild-type HMGA2 and truncated (lacking the 3'UTR) HMGA2 isoforms are overexpressed in several cancers. However, there are no studies investigating the expression and differential roles of WT vs truncated HMGA2 isoforms in prostate cancer. Immunohistochemical staining of prostate tissue microarray revealed low membrane expression in normal epithelial prostate cells, and that expression increased with tumor grade as well as a switch from predominantly cytoplasmic HMGA2 in lower tumor grades, to mostly nuclear in high grade and bone metastatic tissue. LNCaP cells stably overexpressing wild-type HMGA2 displayed nuclear localization of HMGA2 and induction of EMT associated with increased Snail, Twist and vimentin expression compared to LNCaP Neo control cells, as shown by immunofluorescence and western blot analyses. This was associated with increased cell migration on collagen shown using boyden chamber assay. Conversely, LNCaP cells overexpressing truncated HMGA2 showed cytoplasmic HMGA2 expression that did not induce EMT yet displayed increased cell proliferation and migration compared to LNCaP Neo. Both wild-type and truncated HMGA2 increased levels of phospho-ERK, and interestingly, treatment with U0126, MAPK inhibitor, antagonized wild-type HMGA2-mediated EMT and cell migration, but did not affect truncated HMGA2-mediated cell proliferation or migration. Therefore, although both wild-type and truncated HMGA2 may promote prostate tumor progression, wild-type HMGA2 acts by inducing EMT via MAPK pathway.

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Section: Discussionsupporting

confidence: 92%

High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer

Hawsawi

Henderson

Burton

et al. 2018

Biochemical and Biophysical Research Communications

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“…Dynamic intracellular localization processes of HMGA2 mRNA transcripts and translation products have been reported to also influence epithelial tumorigenesis and metastatic potential. Hmga2 expression has been detected in the cell membrane of quiescent non-transformed, post-natal mouse keratinocytes but upon onset of proliferation, membrane-to-nuclear translocation of the protein was observed [176]. Analogous Hmga2 nuclear translocation was also been observed upon ex vivo culture of mouse keratinocytes and during cutaneous carcinogenesis in DMBA and TPA mouse models where Hmga2 induces its own expression in an autoregulatory loop by binding to the Hmga2 promoter [176].…”

Section: Mechanisms Of Hmga2-induced Epithelial Tumorigenicitymentioning

confidence: 98%

“…Hmga2 expression has been detected in the cell membrane of quiescent non-transformed, post-natal mouse keratinocytes but upon onset of proliferation, membrane-to-nuclear translocation of the protein was observed [176]. Analogous Hmga2 nuclear translocation was also been observed upon ex vivo culture of mouse keratinocytes and during cutaneous carcinogenesis in DMBA and TPA mouse models where Hmga2 induces its own expression in an autoregulatory loop by binding to the Hmga2 promoter [176]. Normal human epithelial prostate cell also exhibited low levels of HMGA2 expression in the plasma membrane which switched to predominantly cytoplasmic then nuclear localization with increasing prostate tumor grade, metastatic potential, and HMGA2 expression [177].…”

Section: Mechanisms Of Hmga2-induced Epithelial Tumorigenicitymentioning

confidence: 99%

High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia

Unachukwu

Chada

DʼArmiento

2020

IJMS

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High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.

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“…27 Translocation of HMGA2 from the cell surface to the nucleus caused oncogenic cell transformation on skin carcinomas. 28 To further explore the possibility of diverse prognostic implications of HMGA2 in dependence on specific subcellular localizations, we immunohistochemically evaluated the staining patterns of HMGA2 in a well-characterized cohort of 342 breast cancer patients. Surprisingly, we found a favorable survival probability associated with high levels of HMGA2 in our collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic levels of high mobility group A2 determine survival prognoses in breast cancer patients

et al. 2020

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Background: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. Objective: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. Methods: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. Results: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. Conclusion: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

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Hmga2 translocation induced in skin tumorigenesis

Cited by 7 publications

References 32 publications

High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer

High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer

High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia

Cytoplasmic levels of high mobility group A2 determine survival prognoses in breast cancer patients

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