High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy

Quintavalle, Cristina; Burmeister, Katharina; Piscuoglio, Salvatore; Quagliata, Luca; Karamitopoulou, Eva; Sepe, Romina; Terracciano, Luigi; Andersen, Jesper B.; Pallante, Pierlorenzo; Matter, Matthias S.

doi:10.1002/mc.22671

Cited by 21 publications

(19 citation statements)

References 48 publications

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“…Finally, activation of EMT is also involved in resistance to chemotherapy (MOC-7) 366 . High mobility group A1 protein promoted CCA tumorigenicity and conferred resistance to gemcitabine in vitro in CCA cell lines 388 .…”

Section: Mechanisms Of Chemoresistance (Moc) Accounting Formentioning

confidence: 98%

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Bañales

Marin

Lamarca

et al. 2020

Nat Rev Gastroenterol Hepatol

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Cholangiocarcinoma (CCA) constitutes a diverse group of malignancies emerging in the biliary tree. CCAs are divided into three subtypes depending on their anatomical site of origin: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) CCA 1,2 (Fig. 1). Of note, considered as an independent entity, mixed HCC-CCA tumours are a rare type of liver malignancy sharing features of both iCCA and HCC and presenting an aggressive disease course and poor prognosis 3,4. iCCAs arise above the second-order bile ducts, whereas the point of anatomical distinction between pCCA and dCCA is the insertion of the cystic duct. pCCA and dCCA can also be collectively referred to as 'extrahepatic' (eCCA) 5. In the USA, pCCA is the single largest group, accounting for approximately 50-60% of all CCAs, followed by dCCA (20-30%) and iCCA (10-20%) 1,6,7. CCA is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC), comprising approximately 15% of all primary liver tumours and 3% of gastrointestinal cancers 1,6,7. CCAs are usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis 1,8. CCA is a rare cancer, but its incidence (0.3-6 per 100,000 inhabitants per year) 1 and mortality (1-6 per 100,000 inhabitants per year, globally 9 , not taking into account specific regions with incidence >6 per 100,000 habitants such as South Korea, China and Thailand) have been increasing in the past few decades worldwide, representing a global health problem. Despite advances in

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Section: Mechanisms Of Chemoresistance (Moc) Accounting Formentioning

confidence: 98%

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Bañales

Marin

Lamarca

et al. 2020

Nat Rev Gastroenterol Hepatol

Self Cite

1,500

1,562

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“…Recent studies have revealed that IL-17 overproduction contributes to the inflammatory microenvironment for NSCLC cell proliferation and growth (5,11). Moreover, HMGA1 as a transcription factor and cyclin D1 as a proliferative protein can also promote cancer cell proliferation (40)(41)(42)(43). Hence, in this study, in order to better understand the pathogenesis of IL-17-induced NSCLC cell proliferation, we first detected the level of IL-17 in plasma, and the expression of IL-17R, HMGA1 as well as that of cyclin D1 in the tumor tissues of patients with NSCLC.…”

Section: Disscussionmentioning

confidence: 99%

“…Reportedly, HMGA1 protein acts within the nucleus of mammalian cells as an architectural transcription factor (40,42); however, the cytoplasmic/mitochondrial localization of HMGA1 protein in multiple cell types has also been found (35), suggesting that HMGA1 may undergo nucleocytoplasmic translocation during some biological processes. Moreover, HMGA1 can modulate gene expression by altering the chromatin structure and orchestrating the assembly of transcription factor complexes to augment target gene promoter activity (42).…”

Section: Disscussionmentioning

confidence: 99%

IL‑17 induces NSCLC A549 cell proliferation via the upregulation of HMGA1, resulting in an increased cyclin D1 expression

Zhao

Zhang

et al. 2018

Int J Oncol

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Non-small cell lung cancer (NSCLC) is considered to be an inflammation-associated carcinoma. Although interleukin‑17 (IL‑17) production contributes to the proliferation and growth of NSCLC, the mechanisms underlying IL‑17-induced NSCLC cell proliferation have not been fully elucidated. In the present study, by using ELISA and immunohistochemical analyses, we first found that the expression levels of IL‑17, IL‑17 receptor (IL‑17R), high-mobility group A1 (HMGA1) and cyclin D1 were elevated in the samples of patients with NSCLC. Subsequently, by RT-qPCR, western blot analysis and cell proliferation assay in vitro, we revealed that stimulation with recombinant human IL‑17 (namely IL‑17A) markedly induced the expression of HMGA1 and cyclin D1 in the A549 cells (a human lung adenocarcinoma cell line) and promoted cell proliferation. Furthermore, luciferase reporter and ChIP assays confirmed that upregulated HMGA1 directly bound to the cyclin D1 gene promoter and activated its transcription. Notably, the response element of HMGA1 binding to the cyclin D1 promoter was disclosed for the first time, at least to the best of our knowledge. Taken together, our findings indicate that the IL‑17/HMGA1/cyclin D1 axis plays an important role in NSCLC cell proliferation and may provide new insight into NSCLC pathogenesis and may thus aid in the development of novel therapeutic targets for NSCLC.

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“…Notably, increased expression of HMGA1 signi cantly correlated with the malignant status and prognosis of NSCLC [11]. Interestingly, although it is not lung cancer, recent studies have shown that increased expression of HMGA1 is closely related to the recurrence of various cancers, like hepatocellular carcinoma [12], cholangiocarcinoma [13], and acute lymphoblastic leukemia [14], indicating that elevated HMGA1 plays an important role in cancer recurrence. Together, these ndings suggest that elevated HMGA1 may be involved in the progression of early-stage lung cancer.…”

Section: Introductionmentioning

confidence: 99%

GRP75-mediated upregulation of HMGA1 stimulates stage I lung adenocarcinoma progression by activating the JNK/c-JUN signaling

Qiao

Wang

et al. 2021

Preprint

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Background Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. But the mechanism is largely unknown. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD. Methods The Cancer Genome Atlas (TCGA) dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. Western blotting and immunohistochemistry were used to measure protein expression levels. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis. Results Both HMGA1 expression levels and GRP75 expression levels were associated with recurrence in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor in stage I LUAD patients. Overexpression of GRP75 or HMGA1 significantly stimulated LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis in vitro and in vivo. Importantly, GRP75 inhibited ubiquitination-mediated HMGA1 degradation by directly binding to HMGA1, thereby causes HMGA1 upregulation in LUAD. In addition, the GRP75/HMGA1 axis played its role by activating JNK/c-JUN signaling in LUAD. Conclusions The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and a poor prognosis in stage I LUAD patients.

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High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy

Cited by 21 publications

References 48 publications

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

IL‑17 induces NSCLC A549 cell proliferation via the upregulation of HMGA1, resulting in an increased cyclin D1 expression

GRP75-mediated upregulation of HMGA1 stimulates stage I lung adenocarcinoma progression by activating the JNK/c-JUN signaling

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