Pancreatic Stellate Cells Activation and Matrix Metallopeptidase 2 Expression Correlate With Lymph Node Metastasis in Pancreatic Carcinoma

Li, Yueguang; Song, Tao; Chen, Zhen; Wang, Yao; Zhang, Ju‐Yuan; Wang, Ximo

doi:10.1016/j.amjms.2018.10.001

Cited by 17 publications

(19 citation statements)

References 34 publications

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“…MMP2 is one of the key regulators for the invasion and metastasis of PC (32), and the MMP2 protein expression levels have been associated with lymph node metastasis in PC (54). The present findings suggested that miR-23b-3p could promote liver metastasis of PC cell-derived tumors, possibly via the induction of MMP2.…”

Section: Discussionsupporting

confidence: 49%

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

et al. 2020

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MicroRNA (miR)-23b-3p plays an important role in tumor growth, proliferation, invasion and migration in pancreatic cancer (PC). However, the function and mechanistic role of miR-23b-3p in the development of PC remains largely unknown. In the present study, the miR-23b-3p levels in the serum of patients with PC were found to be elevated, and the phosphorylation levels of Janus kinase (JAK)2, PI3K, Akt and NF-κВ were found to be upregulated. In addition, miR-23b-3p was induced in response to interleukin-6 (IL-6), which is known to be involved in the progression of PC. Overexpression of miR-23b-3p, on the other hand, activated the JAK/PI3K and Akt/NF-κB signaling pathways in PC cells, as evidenced by miR-23b-3p-induced upregulation of phosphorylated (p-) JAK2, p-PI3K, p-Akt and p-NF-κВ, as well as the downregulation of PTEN; and these effects were found to be reversible by miR-23b-3p inhibition. Furthermore, miR-23b-3p was found to downregulate PTEN by directly targeting the 3'-untranslated region of PTEN mRNA. Notably, in an in vivo xenograft mouse model, overexpression of miR-23b-3p accelerated PC cell-derived tumor growth, activated the JAK/Akt/NF-κВ signaling pathway and promoted liver metastasis. In contrast, knockdown of miR-23b-3p suppressed tumor growth and metastasis as well as JAK/Akt/NF-κВ signaling activity. In vivo imaging of the mice further confirmed the metastasis promoting role of miR-23b-3p in PC. These results suggested that miR-23b-3p enhances PC cell tumorigenesis and metastasis, at least, partially via the JAK/PI3K and Akt/NF-κB signaling pathways. Therefore, targeting miR-23b-3p or the JAK/PI3K and Akt/NF-κB signalings may be potential therapeutic strategy against PC.

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Section: Discussionsupporting

confidence: 49%

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

et al. 2020

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“…The most studied MMPs in PDAC are, without a doubt, the gelatinases (MMP2 and MMP9; see Figure 1). The vast majority of studies show that both MMP2 [34,35,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] and MMP9 [34,36,39,48,49,53,54,59,[62][63][64][65][66][67] are upregulated in PDAC patients (Table 1), while a minority of studies fail to show a difference in expression between PDAC and the controls [36,38,52,60,61,[68][69][70][71]. The potential clinical relevance is less pronounced, as just half of the studies reported associations between increased MMP2 or MMP9 levels with clinical characteristics such as survival, metastasis or tumor stage…”

Section: Gelatinases In Pdacmentioning

confidence: 99%

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Slapak

Duitman

Tekin

et al. 2020

Biology

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Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression. Based upon this notion, changes in matrix metalloprotease expression levels are often considered surrogate markers for pancreatic cancer progression and/or treatment response. Indeed, reduced matrix metalloprotease levels upon treatment (either pharmacological or due to genetic ablation) are considered as proof of the anti-tumorigenic potential of the mediator under study. In the current review, we aim to establish whether matrix metalloproteases indeed drive pancreatic cancer progression and whether decreased matrix metalloprotease levels in experimental settings are therefore indicative of treatment response. After a systematic review of the studies focusing on matrix metalloproteases in pancreatic cancer, we conclude that the available literature is not as convincing as expected and that, although individual matrix metalloproteases may contribute to pancreatic cancer growth and metastasis, this does not support the generalized notion that matrix metalloproteases drive pancreatic ductal adenocarcinoma progression.

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“…The levels of members of this family of proteins are increased in pancreatitis and tumors [ 35 ]. Moreover, high levels of MMPs have been related to increased proliferation and migration of PSCs [ 36 ]. Because we had observed that melatonin induced changes in different biomarkers that are related to cell proliferation and that melatonin induced a decrease in cell viability, we decided to evaluate the effect of melatonin on the expression of MMP-2, MMP-3, MMP-9 and MMP-13.…”

Section: Resultsmentioning

confidence: 99%

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

Estarás

Gonzalez

Fernandez–Bermejo

et al. 2021

IJMS

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In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM–1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.

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Pancreatic Stellate Cells Activation and Matrix Metallopeptidase 2 Expression Correlate With Lymph Node Metastasis in Pancreatic Carcinoma

Cited by 17 publications

References 34 publications

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

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Pancreatic Stellate Cells Activation and Matrix Metallopeptidase 2 Expression Correlate With Lymph Node Metastasis in Pancreatic Carcinoma

Cited by 17 publications

References 34 publications

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑&kappa;B signaling pathways

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑&kappa;B signaling pathways

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

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MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways