IL6‐mediated inflammatory loop reprograms normal to epithelial‐mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2‐spectrin+/− mice

Mitra, Abhisek; Yan, Jun; Xia, Xueqing; Zhou, Shouhao; Chen, Jian; Mishra, Lopa; Li, Shulin

doi:10.1002/hep.28951

Cited by 61 publications

(61 citation statements)

References 48 publications

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“…PJA1/wt/LSCs and PJA1/Smad3 þ/À /LSCs were isolated from single mice and immediately seeded and cultured onto 96well plates (3 Â 10 3 cells/well) in suitable supplement-containing medium. Cell proliferation was measured using CyQUANT NF Cell Proliferation Assay reagent at day 1, 3, and 6 as described previously (32). Data are from three independent experiments.…”

Section: Cell Proliferation and Viability Assaymentioning

confidence: 99%

Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

Chen

Mitra

et al. 2020

Cancer Research

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RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFb/SMAD signaling. SMAD3 and its adaptors, such as b2SP, are important mediators of TGFb signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/b2SPdependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3 þ/À), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFb1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFb in liver carcinogenesis.

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Section: Cell Proliferation and Viability Assaymentioning

confidence: 99%

Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

Chen

Mitra

et al. 2020

Cancer Research

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“…which is an important part of tumor progression and metastasis [28]. EMT-related markers such as E-cadherin and EMT transcription factors such as Twist, snail, and slug are important indicators of alterations to the EMT.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Somatostatin Octapeptide Inhibits Cell Invasion and Metastasis in Hepatocellular Carcinoma Through PEBP1

Huang

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hepatocellular carcinoma (HCC) is a major threat to human health. The condition carries a high risk of death; 45% of new cases occur in China. Surgical resection is the first choice for treatment of HCC, but 30.9% of patients experience recurrence within 6 months after the operation. To improve patient survival, we must determine how to reduce the probability of recurrence and metastasis and elucidate the underlying mechanism of disease. We therefore studied the effect of somatostatin octapeptide (octreotide) on the invasion and metastasis of HCC. Methods: The migration and invasion cytological tests were used to detect the effect of octreotide on liver cancer cells (SK-Hep-1 and HepG2). PEBP1 RNAi was used to knockdown expression. Invasion and metastasis were measured with transwell migration and wound-healing assays. Western blotting was used to detect changes in levels of PEBP1 and invasion pathway proteins after octreotide treatment. The effect of octreotide was studied in vivo by establishing a pulmonary metastasis model using SK-Hep-1 cells in nude mice. In-vivo bioluminescence imaging and hematoxylin and eosin staining of lung tissue were used to verify the results. Results: Increasing concentrations of octreotide were progressively more effective in halting the invasion and metastasis of liver cancer cells. Octreotide may upregulate PEBP1, TIMP-2, and E-cadherin while downregulating MMP-2 and Twist to inhibit cell invasion and metastasis. And downregulation of PEBP1 would also change the expression of MMP-2, TIMP-2 and Twist. The in-vivo experiments showed no cancer cell metastasis in 4 of the 6 mice in the octreotide-treatment group, while all of the mice in the control group displayed pulmonary metastasis of human HCC cells. And the survival period of the mice in the octreotide-treatment group was significantly prolonged. Conclusions: Octreotide may weaken invasion and metastasis through the upregulation of PEBP1. Octreotide may reduce the risk of recurrence and metastasis after surgery for liver cancer.

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“…Increased IL-6 expression has been reported to drive CSCs expansion through STAT3 activation in HCC [118] . Moreover, a recent study has demonstrated that EMT+ metastatic CSCs can be generated in a β2SP +/mouse model of HCC, mainly due to overexpression of IL-6 in addition to the partial disruption of TGF-β signaling [119] .…”

Section: Janus Kinase/signal Transducers and Activators Of Transcriptmentioning

confidence: 99%

Stemness features in liver cancer

Correnti¹,

Booijink²,

Maira³

et al. 2018

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Heterogeneity is a cardinal hallmark of cancer, including primary liver cancer (PLC), and occurs at different layers including putative cell-of-origin. Current evidence suggests that within cellular subpopulations in PLC there are stem-like cells, the cancer stem cells (CSCs). The CSC concept has been recently proposed as an explanation of such intra-tumor heterogeneity. According to this model, CSCs are responsible for tumor initiation, recurrence, metastasis as well as drug-resistance. However, although the CSC hypothesis is intriguing and supported by a large number of experimental studies, there are still open questions regarding the origin of putative CSCs. Since chemoresistance and recurrence represent major issues in PLC treatment, the development of new therapeutic strategies is needed, for which a good understanding of tumor behavior and in particular of CSCs biology is an imperative prerequisite. In this review we summarize the regulatory pathways that support CSC features in PLC. Moreover, we highlight the key features of hepatic CSC, in terms of enhanced drug-resistance, increased metastatic potential and metabolic rearrangement. Knowledge of the molecular mechanisms underlying CSC biology may provide novel options for PLC combination therapies.Primary liver cancer (PLC) is one of the most common cancers worldwide and the second leading cause of cancer-related mortality [1,2] . The major forms of PLC comprise hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) [1,3-5] . HCC accounts for approximately 90% of all PLCs [1,3] , while CCA is the second most common form and accounts for about 5% of all PLCs [3][4][5] . HCC causes over 600,000 deaths worldwide annually, and its incidence and mortality are increasing at a fast rate [6-10] . On the other hand, CCA is characterized by a very poor prognosis, with a 5-years survival lower than 20%, and its incidence and worldwide mortality are also increasing [5,[11][12][13] . The high mortality rate of CCA may depend on its nonspecific or silent clinical features and the lack of specific markers that make it difficult to diagnose [14][15][16] .Many studies carried out in these last years have attempted to define which type of epithelial cell [hepatocytes, cholangiocytes, hepatic progenitor cells (HPCs) or all three] should be considered as the PLC cell of origin [17] . For a long time, HCC and CCA have been commonly accepted to derive from hepatocytes and cholangiocytes, respectively. Since mature hepatocytes and cholangiocytes have an enormous selfrenewal capacity and longevity, they meet the requirements to be targets for oncogenesis [17][18][19][20][21][22][23] . Detailed analyses of a wide range of PLC tumor types have reported that a rare form of combined HCC-CCA (cHCC-CCA) has intermediate characteristics between HCC and intrahepatic CCA (iCCA), suggesting that they could share the same stem/progenitor cell origin [18][19][20][21][22][23][24] . In this regard, since most PLCs arise on the background of chronic liver disease in the presence of an ex...

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IL6‐mediated inflammatory loop reprograms normal to epithelial‐mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2‐spectrin+/− mice

Cited by 61 publications

References 48 publications

Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

Somatostatin Octapeptide Inhibits Cell Invasion and Metastasis in Hepatocellular Carcinoma Through PEBP1

Stemness features in liver cancer

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