Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression.

Stem cells persist throughout life in diverse tissues by undergoing self-renewing divisions. Self-renewal capacity declines with age, partly because of increasing expression of the tumor suppressor p16(Ink4a). We discovered that the Hmga2 transcriptional regulator is highly expressed in fetal neural stem cells but that expression declines with age. This decrease is partly caused by the increasing expression of let-7b microRNA, which is known to target HMGA2. Hmga2-deficient mice show reduced stem cell numbers and self-renewal throughout the central and peripheral nervous systems of fetal and young-adult mice but not old-adult mice. Furthermore, p16(Ink4a) and p19(Arf) expression were increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16(Ink4a) and/or p19(Arf) partially restored self-renewal capacity. let-7b overexpression reduced Hmga2 and increased p16(Ink4a)/p19(Arf) expression. Hmga2 thus promotes fetal and young-adult stem cell self-renewal by decreasing p16(Ink4a)/p19(Arf) expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural stem cell function.

High mobility group AT-hook 2 regulates osteoblast differentiation and facial bone development.

The mutation and deletion of high mobility group AT-hook 2 (Hmga2) gene exhibit skeletal malformation, but almost nothing is known about the mechanism. This study examined morphological anomaly of facial bone in Hmga2-/- mice and osteoblast differentiation of pre-osteoblast MC3T3-E1 cells with Hmga2 gene knockout (A2KO). Hmga2-/- mice showed the size reduction of anterior frontal part of facial bones. Hmga2 protein and mRNA were expressed in mesenchymal cells at ossification area of nasal bone. A2KO cells differentiation into osteoblasts after reaching the proliferation plateau was strongly suppressed by alizarin red and alkaline phosphatase staining analyses. Expression of osteoblast-related genes, especially Osterix, was down-regulated in A2KO cells. These results demonstrate a close association of Hmga2 with osteoblast differentiation of mesenchymal cells and bone growth. Although future studies are needed, the present study suggests an involvement of Hmga2 in osteoblast-genesis and bone growth.

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

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.

Hmga2 regulation of tooth formation and association with Sox2 and Nanog expression.

Tooth formation is accomplished under strict genetic programs. Although patients with chromosome 12q14 aberration shows tooth phenotype including the size and eruption timing with bone growth anomaly, its etiology is uncertain. Here, we examined expression of Hmga2, which is encoded at chromosome 12q14, in mouse tooth germs and analyzed the involvement in lower first molar (M1) and mandibular bone development. Hmga2 expression was immunohistochemically detected at enamel organ and the surrounding mesenchyme of the M1 germs. The expression was dynamically changed with gestation and rapidly decreased in postnatal mice. In Hmga2-/- mice, the M1 germs and crowns were diminished in size, and formation and eruption of molars were delayed with mandibular bone growth retardation. Hmga2 cDNA or siRNA transfection showed that Hmga2 transcriptionally up-regulates expression of stem cell factors, Sox2 and Nanog. They were co-localized with Hmga2 in the germs, but differentially distributed at enamel organ and mesenchyme in Hmga2-/- mice. These results demonstrate that Hmga2 expressed in tooth germs regulates the growth, sizing and eruption and stem cell factor expression in different compartment of the germ and associates with mandibular bone growth. Although future studies are needed, the present study demonstrates HMGA2 regulation of tooth genesis with skeletal development.

HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis.

The ten-eleven translocation (TET) family of methylcytosine dioxygenases initiates demethylation of DNA and is associated with tumorigenesis in many cancers; however, the mechanism is mostly unknown. Here we identify upstream activators and downstream effectors of TET1 in breast cancer using human breast cancer cells and a genetically engineered mouse model. We show that depleting the architectural transcription factor high mobility group AT-hook 2 (HMGA2) induces TET1. TET1 binds and demethylates its own promoter and the promoter of homeobox A (HOXA) genes, enhancing its own expression and stimulating expression of HOXA genes including HOXA7 and HOXA9. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts. The genes comprising the HMGA2-TET1-HOXA9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. These results implicate the HMGA2-TET1-HOX signaling pathway in the epigenetic regulation of human breast cancer and highlight the importance of targeting methylation in specific subpopulations as a potential therapeutic strategy.

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling.

Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AT-hook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/ß-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

Tyrosine Kinase Inhibitors Diminish Renal Neoplasms in a Tuberous Sclerosis Model Via Induction of Apoptosis.

Tuberous sclerosis complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition because recurrence of disease occurs after treatment is discontinued. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage-specific platelet-derived growth factor receptor ß (PDGFRß) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin-induced versus tyrosine kinase inhibitor (TKI)-induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, RNA sequencing, and bioinformatics to distinguish tumoricidal mechanisms adopted by each drug type. The efficacy of imatinib therapy was validated against spontaneously developing renal cystadenomas in tuberous sclerosis Tsc2+/- mouse models (C57BL/6J mice; N = 6; 400 mg/kg/d; oral gavage) compared with Tsc2+/- mice treated with PBS (C57BL/6J mice; N = 6). Our study revealed that TKIs imatinib and nilotinib were cytocidal to both pulmonary LAM and renal AML cell cultures through the downregulation of the glycoprotein GPVI pathway and resultant disruption in mitochondrial permeability, increased cytosolic cytochrome C, and caspase 3 activation. Importantly, renal tumor growth was significantly attenuated in imatinib-treated Tsc2+/- mice compared with PBS treatment. The preclinical studies reported here provide evidence documenting the effectiveness of TKIs in limiting LAM and AML cell growth and viability with important clinical potential. Furthermore, these drugs elicit their effects by targeting a PDGF pathway-dependent apoptotic mechanism supporting the investigation of these drugs as a novel class of TSC therapeutics.

In vivo modulation of HMGA2 expression.

While the biochemical role of the HMGA proteins has largely been elucidated in tissue culture, the majority of the insight as to their physiological functions in the processes of proliferation and development has been established in animal models of overexpression (transgenic) and null mice (knockouts). An emphasis has been placed on the HMGA2 studies which have defined its critical role in mesenchymal proliferation and differentiation.

Renal neoplasms in tuberous sclerosis mice are neurocristopathies.

Tuberous sclerosis (TS) is a rare disorder exhibiting multi-systemic benign neoplasms. We hypothesized the origin of TS neoplastic cells derived from the neural crest given the heterogeneous ecto-mesenchymal phenotype of the most common TS neoplasms. To test this hypothesis, we employed Cre-loxP lineage tracing of myelin protein zero (Mpz)-expressing neural crest cells (NCCs) in spontaneously developing renal tumors of Tsc2 +/- /Mpz(Cre)/TdT fl/fl reporter mice. In these mice, ectopic renal tumor onset was detected at 4 months of age increasing in volume by 16 months of age with concomitant increase in the subpopulation of tdTomato+ NCCs from 0% to 6.45% of the total number of renal tumor cells. Our results suggest that Tsc2 +/- mouse renal tumors arise from domiciled proliferative progenitor cell populations of neural crest origin that co-opt tumorigenesis due to mutations in Tsc2 loci. Targeting neural crest antigenic determinants will provide a potential alternative therapeutic approach for TS pathogenesis.

Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis.

The normal expression pattern of HMGA2, an architectural transcription factor, is primarily restricted to cells of the developing mesenchyme before their overt differentiation during organogenesis. A detailed in situ hybridization analysis showed that the undifferentiated mesoderm of the embryonic lung expressed Hmga2 but it was not expressed in the newborn or adult lung. Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. Here, we show that HMGA2 is misexpressed in pulmonary lymphangiomyomatosis (LAM), a severe disorder of unknown etiology consisting of lymphatic smooth muscle cell proliferation that results in the obstruction of airways, lymphatics, and vessels. Immunohistochemistry was done with antibodies to HMGA2 and revealed expression in lung tissue samples obtained from 21 patients with LAM. In contrast, HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation. In vivo studies in transgenic mice show that misexpression of HMGA2 in smooth muscle cells resulted in increased proliferation of these cells in the lung surrounding the epithelial cells. Therefore, similar to the other mesenchymal neoplasms, HMGA2 misexpression in the smooth muscle cell leads to abnormal proliferation and LAM tumorigenesis. These results suggest that HMGA2 plays a central role in the pathogenesis of LAM and is a potential candidate as a therapeutic target.

Misexpression of full-length HMGA2 induces benign mesenchymal tumors in mice.

The high-mobility group AT-hook 2 (HMGA2) protein is a member of the high-mobility group family of the DNA-binding architectural factors and participates in the conformational regulation of active chromatin on its specific downstream target genes. HMGA2 is expressed in the undifferentiated mesenchyme and is undetectable in their differentiated counterparts, suggesting its functional importance in mesenchymal cellular proliferation and differentiation. Interestingly, it is a frequent target of chromosomal translocations in several types of human benign differentiated mesenchymal tumors, including lipomas, fibroadenomas of the breast, salivary gland adenomas, and endometrial polyps. The translocations lead to a variety of HMGA2 transcripts, which range from wild-type, truncated, and fusion mRNA species. However, it is not clear whether alteration of the HMGA2 transcript is required for its tumorigenic potential. To determine whether misexpression of HMGA2 in differentiated mesenchymal cells is sufficient to cause tumorigenesis, we produced transgenic mice that misexpressed full-length or truncated human HMGA2 transcript under the control of the differentiated mesenchymal cell (adipocyte)-specific promoter of the adipocyte P2 (Fabp4) gene. Expression of the full-length HMGA2 transgene was observed in a number of tissues, which produced neoplastic phenotype, including fibroadenomas of the breast and salivary gland adenomas. Furthermore, transgenic misexpression of the truncated version of HMGA2, containing only the three DNA-binding domains, produced similar phenotypes. These results show that misexpression of HMGA2 in a differentiated mesenchymal cell is sufficient to cause mesenchymal tumorigenesis and is independent of the nature of the HMGA2 transcript that results from chromosomal translocations observed in humans.

Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity.

Carcinoma cells of epithelial origin are predisposed to acquire a fibroblastic feature during progression of neoplasm referred to as the epithelial-mesenchymal transition. HMGA2 is an architectural transcriptional factor that is expressed in the undifferentiated mesenchyme and initiates mesenchymal tumor formation. However, the biological consequence of the expression in the pathology of epithelial-type carcinomas is controversial. The present study was conducted to dissect the expression pattern in oral squamous cell carcinomas. HMGA2 was detected exclusively in carcinoma cell lines and tissues, but not in normal keratinocytes and gingival, by conventional reverse transcription-PCR. Quantitative real-time reverse transcription-PCR demonstrated 160-fold more HMGA2 expression in carcinoma tissues than in normal gingiva and 11-fold more HMGA2 expression in carcinoma cell lines than in normal keratinocytes. HMGA2 expression was observed by immunohistochemistry in 73.8% of 42 carcinomas and localized to the invasive front, where the cells exhibit the epithelial-mesenchymal transition. Fourteen patients who had been classified into a group without lymph node metastasis were positive for HMGA2 staining, and the disease recurred. Furthermore, carcinomas from all 23 patients who died of tumor recurrence stained for HMGA2, and HMGA2 staining was correlated to long-term survival of patients (P < 0.01). Multivariate risk factor analysis demonstrated that HMGA2 expression was an independent prognostic value for disease-specific overall survival (P < 0.01). These results suggest that HMGA2 contributes to the aggressiveness of carcinoma and that detection of HMGA2 expression is a useful predictive and prognostic tool in clinical management of oral carcinomas.

Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation.

Tuberous sclerosis (TSC) is a tumor suppressor gene syndrome that is associated with the widespread development of mesenchymal tumor types. Genetically, TSC is said to occur through a classical biallelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is implicated in the induction of the mTOR pathway and subsequent tumorigenesis. High Mobility Group A2 (HMGA2), an architectural transcription factor, is known to regulate mesenchymal differentiation and drive mesenchymal tumorigenesis in vivo. Here, we investigated the role of HMGA2 in the pathogenesis of TSC using the TSC2(+/-) mouse model that similarly mirrors human disease and human tumor samples. We show that HMGA2 expression was detected in 100% of human and mouse TSC tumors and that HMGA2 activation was required for TSC mesenchymal tumorigenesis in genetically engineered mouse models. In contrast to the current dogma, the mTOR pathway was not activated in all TSC2(+/-) tumors and was elevated in only 50% of human mesenchymal tumors. Moreover, except for a subset of kidney tumors, tuberin was expressed in both human and mouse tumors. Therefore, haploinsufficiency of one TSC tumor suppressor gene was required for tumor initiation, but further tumorigenesis did not require the second hit, as previously postulated. Collectively, these findings demonstrate that tissue-specific genetic mechanisms are employed to promote tumor pathogenesis in TSC and identify a novel, critical pathway for potential therapeutic targeting.

Molecular characterization of the mouse In(10)17Rk inversion and identification of a novel muscle-specific gene at the proximal breakpoint.

Chromosomal rearrangements provide an important resource for molecular characterization of mutations in the mouse. In(10)17Rk mice contain a paracentric inversion of approximately 50 Mb on chromosome 10. Homozygous In(10)17Rk mice exhibit a pygmy phenotype, suggesting that the distal inversion breakpoint is within the pygmy locus. The pygmy mutation, originally isolated in 1944, is an autosomal recessive trait causing a dwarf phenotype in homozygous mice and has been mapped to the distal region of chromosome 10. The pygmy phenotype has subsequently been shown to result from disruption of the Hmgi-c gene. To identify the In(10)17Rk distal inversion breakpoint, In(10)17Rk DNA was subjected to RFLP analysis with single copy sequences derived from the wild-type pygmy locus. This analysis localized the In(10)17Rk distal inversion breakpoint to intron 3 of Hmgi-c and further study determined that a fusion transcript between novel 5' sequence and exons 4 and 5 of Hmgi-c is created. We employed 5' RACE to isolate the 5' end of the fusion transcript and this sequence was localized to the proximal end of chromosome 10 between markers Cni-rs2 and Mtap7. Northern blot analysis of individual tissues of wild-type mice determined that the gene at the In(10)17Rk proximal inversion breakpoint is a novel muscle-specific gene and its disruption does not lead to a readily observable phenotype.

Pleomorphic adenoma (benign mixed tumor) of the breast: a case report and review of the literature.

We report a case of pleomorphic adenoma (benign mixed tumor) of the breast, which is an extremely rare location for this tumor. Examination of a 55-year-old woman unexpectedly revealed a mass measuring 0.8 cm in diameter in the subareolar region of the right breast. Excisional biopsy was performed, and the tumor histologically showed pleomorphic adenoma composed of duct epithelial cells, myoepithelial cells, and a myxochondroid matrix. Immunohistochemically, duct epithelial cells were positive for the estrogen receptor, but negative for the progesterone receptor. The nuclei of the spindle and myoepithelial cells were immunoreactive for HMGI-C and HMGI(Y) proteins, indicating a histogenesis similar to pleomorphic adenoma of the salivary glands. Interphase fluorescence in situ hybridization performed on paraffin-embedded tissue sections with 12q15 probes and a 6p21 probe demonstrated no chromosomal rearrangement. Sixty-nine cases of this type of tumor arising in the breast have been described previously. Using imaging procedures, the tumor has occasionally been misdiagnosed as malignant clinically and even pathologically in frozen section diagnosis. Careful diagnosis based on paraffin sections is required to avoid unnecessary aggressive surgery, and pathologists should include pleomorphic adenoma in the differential diagnosis of a demarcated, juxtaareolar, small hard mass.

Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.

Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP(+) tumors, relative to metastatic RKIP(-) tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP(+) tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics.

Differential regulation of the insulin-like growth factor II mRNA-binding protein genes by architectural transcription factor HMGA2.

The developmentally regulated architectural transcription factor, high mobility group A2 (HMGA2), is involved in growth regulation and plays an important role in embryogenesis and tumorigenesis. Little is known, however, about its downstream targets. We performed a search for genes of which expression is strongly altered during embryonic development in two HMGA2-deficient mouse strains, which display a pygmy-phenotype, as compared to wild-type mice. We found that the insulin-like growth factor II mRNA-binding protein 2 gene (IMP2), but not its family members IMP1 and IMP3, was robustly downregulated in mutant E12.5 embryos. Furthermore, we show that wild-type HMGA2 and its tumor-specific truncated form have opposite effects on IMP2 expression. Our results clearly indicate that HMGA2 differentially regulates expression of IMP family members during embryogenesis.

HMGA2 is expressed in an allele-specific manner in human lipomas.

The architectural transcription factor HMGA2 is almost exclusively expressed in undifferentiated mesenchymal cells. Interestingly, it has been mapped to the translocation site in a variety of human mesenchymal tumors that reveal a terminally differentiated phenotype. The expression of chimeric HMGA2 transcripts encoding three DNA-binding domains fused to novel transcriptional regulatory domains was previously described in lipomas. In this study with lipoma ST91-198, we report the expression of truncated HMGA2 transcripts that gained no functional domains. The highly polymorphic region in the 5' untranslated region (UTR) of HMGA2 was used to determine the allele-specific expression of HMGA2 in lipomas. Microsatellite PCR revealed a monoallelic expression pattern, and only the translocated allele was expressed when the DNA-binding domains of the rearranged allele were fused with transcription activation domains. Surprisingly, a diallelic expression pattern of HMGA2 was observed in lipoma ST91-198, and the wild-type allele was also expressed. In conjunction with studies involving rearrangements of HMGA genes in other benign mesenchymal tumors, our results support a model in which the expression of the wild-type HMGA allele is critical for the pathogenesis of mesenchymal tumors and in which rearrangements of HMGA do not lead to a gain of function in the chimeric HMGA protein.

High mobility group I-C protein in astrocytoma and glioblastoma.

High mobility group I-C (HMGI-C) protein is a non-histone DNA-binding factor that organizes active chromatin. This protein is expressed during the limited phase of embryonic development and may regulate the expression of genes critical for embryonic cell growth and differentiation. As embryonic mechanisms are also known to play a role in the development of some neoplasms, we investigated human brain tumors for the expression of HMGI-C to determine its role in the differentiation of glial cell tumors. Immunohistochemical analysis revealed HMGI-C in all of the low-grade astrocytomas, in 2 of 3 anaplastic astrocytomas (grade 3), but in only one of 8 glioblastomas. The results were confirmed at the mRNA level by nested reverse-transcription polymerase chain reaction analyses. Loss of HMGI-C was also demonstrated in a case of glioblastoma transformed from the low-grade astrocytoma strongly expressing HMGI-C protein. These results suggest that HMGI-C may be involved in the differentiation of glial tumor cells, and that loss of HMGI-C expression may contribute to the transformation of low-grade astrocytoma into glioblastoma.

HMGA2 is a driver of tumor metastasis.

The non-histone chromatin-binding protein HMGA2 is expressed predominantly in the mesenchyme before its differentiation, but it is also expressed in tumors of epithelial origin. Ectopic expression of HMGA2 in epithelial cells induces epithelial-mesenchymal transition (EMT), which has been implicated in the acquisition of metastatic characters in tumor cells. However, little is known about in vivo modulation of HMGA2 and its effector functions in tumor metastasis. Here, we report that HMGA2 loss of function in a mouse model of cancer reduces tumor multiplicity. HMGA2-positive cells were identified at the invasive front of human and mouse tumors. In addition, in a mouse allograft model, HMGA2 overexpression converted nonmetastatic 4TO7 breast cancer cells to metastatic cells that homed specifically to liver. Interestingly, expression of HMGA2 enhanced TGFß signaling by activating expression of the TGFß type II receptor, which also localized to the invasive front of tumors. Together our results argued that HMGA2 plays a critical role in EMT by activating the TGFß signaling pathway, thereby inducing invasion and metastasis of human epithelial cancers.