Honokiol Suppresses Perineural Invasion of Pancreatic Cancer by Inhibiting SMAD2/3 Signaling

BackgroundPerineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.MethodsIn our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.ResultsWe found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.ConclusionOur results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.

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Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer ◽

10.1186/s12885-020-07722-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Fumihiko Matsuzawa ◽

Hirofumi Kamachi ◽

Tatsuzo Mizukami ◽

Takahiro Einama ◽

Futoshi Kawamata ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Cancer Cell ◽

Morphological Changes ◽

Pancreatic Cancer Cells ◽

Cell Invasiveness ◽

And Migration ◽

Migration Capacity

Abstract Background Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. Methods We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. Results Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. Conclusions Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

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NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Feng Guo ◽

Yingke Zhou ◽

Hui Guo ◽

Dianyun Ren ◽

Xin Jin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Transcriptional Activation ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Gene Sets ◽

And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

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LAMC2 modulates the acidity of microenvironments to promote invasion and migration of pancreatic cancer cells via regulating AKT-dependent NHE1 activity

Experimental Cell Research ◽

10.1016/j.yexcr.2020.111984 ◽

2020 ◽

Vol 391 (1) ◽

pp. 111984 ◽

Cited By ~ 1

Author(s):

Hui Wang ◽

Jun Cai ◽

Shaoxia Du ◽

Wei Wei ◽

Xiaohong Shen

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Invasion And Migration ◽

Pancreatic Cancer Cells ◽

Nhe1 Activity ◽

And Migration

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CCL18 promotes epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells in pancreatic ductal adenocarcinoma

International Journal of Oncology ◽

10.3892/ijo.2014.2794 ◽

2014 ◽

Vol 46 (3) ◽

pp. 1109-1120 ◽

Cited By ~ 40

Author(s):

FANBIN MENG ◽

WAN LI ◽

CHANGLING LI ◽

ZHIGANG GAO ◽

KEJIAN GUO ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Ductal Adenocarcinoma ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Pancreatic Cancer Cells ◽

And Migration

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Human bone marrow mesenchymal stem cells-derived microRNA-205-containing exosomes impede the progression of prostate cancer through suppression of RHPN2

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1488-1 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 7

Author(s):

Shuangjian Jiang ◽

Chengqiang Mo ◽

Shengjie Guo ◽

Jintao Zhuang ◽

Bin Huang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Proliferation ◽

Prostate Cancer Cells ◽

Invasion And Migration ◽

And Migration

Abstract Background Human bone marrow mesenchymal stem cells (hBMSCs) are implicated in cancer initiation and metastasis, sometimes by releasing exosomes that mediate cell communication by delivering microRNAs (miRNAs). This study aimed to investigate the physiological mechanisms by which exosomal miR-205 derived from hBMSCs may modulate the growth of prostate cancer cells. Methods Microarray-based gene expression profiling of prostate cancer was adopted to identify differentially expressed genes and regulatory miRNAs, which identified the candidates RHPN2 and miR-205 as the study focus. Then the binding affinity between miR-205 and RHPN2 was identified using in silico analysis and luciferase activity detection. Prostate cancer cells were co-cultured with exosomes derived from hBMSCs treated with either miR-205 mimic or miR-205 inhibitor. Subsequently, prostate cancer cell proliferation, invasion, migration, and apoptosis were detected in vitro. The effects of hBMSCs-miR-205 on tumor growth were investigated in vivo. Results miR-205 was downregulated, while RHPN2 was upregulated in prostate cancer cells. RHPN2 was a target of miR-205, and upregulated miR-205 inhibited prostate cancer cell proliferation, invasion, and migration and promoted apoptosis by targeting RHPN2. Next, experiments demonstrated that hBMSCs-derived exosomes carrying miR-205 contributed to repressed prostate cancer cell proliferation, invasion, and migration and enhanced apoptosis. Furthermore, in vivo assays confirmed the inhibitory effects of hBMSCs-derived exosomal miR-205 on prostate cancer. Conclusion The hBMSCs-derived exosomal miR-205 retards prostate cancer progression by inhibiting RHPN2, suggesting that miR-205 may present a predictor and potential therapeutic target for prostate cancer.

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