Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

Strell, Carina; Norberg, K. Jessica; Mezheyeuski, Artur; Schnittert, Jonas; Kuninty, Praneeth R.; Moro, Carlos Fernández; Paulsson, Janna; Schultz, Nicolai Aagaard; Calatayud, Dan; Löhr, Matthias; Frings, Oliver; Verbeke, Caroline; Heuchel, Rainer; Prakash, Jai; Johansen, Julia S.; Östman, Arne

doi:10.1038/bjc.2017.140

Cited by 37 publications

(38 citation statements)

References 65 publications

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“…In fact, our recent single molecule study revealed that HMGA2 can stabilize hairpins that are formed in single stranded DNA regions (28). In this context, it is noteworthy that our data correlates with a recent extensive in vivo study that implicates HMGA2 expression as a prognostic factor to poor clinical outcomes in human pancreatic cancer patients treated with DNA synthesis inhibitors (58).…”

Section: Discussionsupporting

confidence: 84%

The chromatin structuring protein HMGA2 influences human subtelomere stability and cancer chemosensitivity

Ahmed

Ramani

Rong

et al. 2019

Preprint

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4The transient build-up of DNA supercoiling during the translocation of replication forks 3 5 threatens genome stability and is controlled by DNA topoisomerases (TOPs). This crucial 3 6 process has been exploited with TOP poisons for cancer chemotherapy. However, 3 7 pinpointing cellular determinants of the best clinical response to TOP poisons still remains 3 8 enigmatic. Here, we present an integrated approach and demonstrate that endogenous and 3 9 exogenous expression of the oncofetal high-mobility group AT-hook 2 (HMGA2) protein 4 0 exhibited broad protection against the formation of hydroxyurea-induced DNA breaks in 4 1 various cancer cells, thus corroborating our previously proposed model in which HMGA2 4 2 functions as a replication fork chaperone that forms a protective DNA scaffold at or close to 4 3 stalled replication forks. We now further demonstrate that high levels of HMGA2 also 4 4 protected cancer cells against DNA breaks triggered by the clinically important TOP1 poison 4 5 irinotecan. This protection is most likely due to the recently identified DNA supercoil 4 6 constraining function of HMGA2 in combination with exclusion of TOP1 from binding to 4 7 supercoiled substrate DNA. In contrast, low to moderate HMGA2 protein levels surprisingly 4 8 potentiated the formation of irinotecan-induced genotoxic covalent TOP1-DNA cleavage 4 9 8 1

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Section: Discussionsupporting

confidence: 84%

The chromatin structuring protein HMGA2 influences human subtelomere stability and cancer chemosensitivity

Ahmed

Ramani

Rong

et al. 2019

Preprint

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“…To investigate whether knockdown of ITGA5 in hPSCs retards their pro-tumorigenic effects in vivo, we established a co-injection tumor model in immunodeficient SCID mice. As consistent with previous reports 12,30 , tumors derived from co-injection of PANC-1 and hPSCs showed a significant increased tumor growth compared to tumors with PANC-1 cells alone ( Fig. 4D).…”

Section: Itga5 Knockdown Inhibits Psc-induced Paracrine Effect In Vitsupporting

confidence: 92%

Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

Bansal

et al. 2018

Preprint

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Pancreatic stellate cells (PSCs) are the main precursors of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC), known to induce cancer aggressiveness. Integrin alpha5 (ITGA5), a fibronectin receptor, was found to be overexpressed by CAFs in stroma and linked to poor overall survival (log-rank p=0.022, n=137) of patients with PDAC. In vitro, knockdown of ITGA5 in human PSCs (hPSCs) inhibited their adhesion, migration, and proliferation and also inhibited TGF-b-mediated differentiation. In vivo, co-injection of PANC-1 tumor cells and hPSCs (sh-ITGA5) developed tumors with reduced fibrosis and slower growth rate compared to those composed of PANC-1 and hPSC (sh-Ctrl). Furthermore, we developed a ITGA5-antagonizing peptidomimetic (AV3) which inhibited TGFb-mediated hPSC differentiation by blocking ITGA5/FAK pathway. In vivo, treatment with AV3 intraperitoneally attenuated tumor fibrosis and thereby enhanced the efficacy of gemcitabine in patient-derived xenografts in mice.Altogether, this study reports the therapeutic importance of ITGA5 in PDAC and provides novel therapeutic peptidomimetic to enhance the effect of chemotherapy.

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“…These results suggest that HMGA2 acts as a target gene of many micro RNAs (miRNAs) and lncRNAs, which play critical roles in regulating tumorigenesis and cancer progression. In addition, several recent studies demonstrated that HMGA2 overexpression, both in the tissues and blood of patients with cancer correlated with poor tumor differentiation, positive lymph node metastasis, and advanced stage, indicating a poor prognosis [ 46 , 47 ]. As a member of the HMGA protein family, HMGA1 also has been reported to be overexpressed in cancers and promote tumorigenesis [ 48 – 51 ].…”

Section: Discussionmentioning

confidence: 99%

High mobility group protein A2 overexpression indicates poor prognosis for cancer patients: a meta-analysis

et al. 2017

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Overexpression of the high mobility group protein A2 (HMGA2), an architectural transcription factor, has been linked to poor prognosis in many malignancies, although this remains controversial. Herein, we conducted a meta-analysis to investigate whether HMGA2 has prognostic value, and evaluated the association between HMGA2 and clinicopathologic factors in malignancies. A total of 29 studies involving 4114 patients were included in this meta-analysis. The pooled results demonstrated that elevated HMGA2 predicted a poor overall survival (OS) (hazard ratio [HR] = 1.82; 95% confidence interval [CI] = 1.62–2.05; P < 0.001) and disease-free survival/progression-free survival/recurrence-free survival (HR = 1.94; 95% CI = 1.27–2.98; P = 0.002). Subgroup analysis conducted by study region, sample size, detection method, and analysis method indicated that HMGA2 overexpression correlated with poor OS. Furthermore, HMGA2 overexpression was found to be linked to poor OS in various cancers except ovarian cancer (pooled HR = 1.14; 95% CI = 0.62–2.09; P = 0.673). High HMGA2 expression level also correlated with advanced TNM stage (OR = 2.44; 95% CI =1.87–3.2; P < 0.001), lymphovascular invasion (OR = 2.46, 95% CI = 1.67–3.64; P < 0.001), distant metastasis (OR = 2.66; 95% CI =1.51–4.69; P < 0.001), and lymph node metastasis (OR = 1.83; 95% CI =1.27–2.64; P = 0.001). In conclusion, HMGA2 overexpression indicates a worse prognosis and may serve as a prognostic predictor in cancer patients.

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Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

Cited by 37 publications

References 65 publications

The chromatin structuring protein HMGA2 influences human subtelomere stability and cancer chemosensitivity

The chromatin structuring protein HMGA2 influences human subtelomere stability and cancer chemosensitivity

Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

High mobility group protein A2 overexpression indicates poor prognosis for cancer patients: a meta-analysis

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