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20 pages, 15002 KiB

Open AccessArticle

Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis

by Jiaping Chen, Yangwei Wang, Wangyang Meng, Rong Zhao, Wei Lin, Han Xiao and Yongde Liao

Int. J. Mol. Sci. 2023, 24(7), 6826; https://doi.org/10.3390/ijms24076826 - 6 Apr 2023

Cited by 3 | Viewed by 1930

Abstract

Metastases contribute to the low survival rate of non-small cell lung cancer (NSCLC) patients. Targeting lipid metabolism for anticancer therapies is attractive. Accumulative evidence shows that stearoyl-CoA desaturases1 (SCD1), a key enzyme in lipid metabolism, enables tumor metastasis and the underlying mechanism remains [...] Read more.

Metastases contribute to the low survival rate of non-small cell lung cancer (NSCLC) patients. Targeting lipid metabolism for anticancer therapies is attractive. Accumulative evidence shows that stearoyl-CoA desaturases1 (SCD1), a key enzyme in lipid metabolism, enables tumor metastasis and the underlying mechanism remains unknown. In this study, immunohistochemical staining of 96 clinical specimens showed that the expression of SCD1 was increased in tumor tissues (p < 0.001). SCD1 knockdown reduced the migration and invasion of HCC827 and PC9 cells in transwell and wound healing assays. Aromatase (CYP19A1) knockdown eliminated cell migration and invasion caused by SCD1 overexpression. Western blotting assays demonstrated that CYP19A1, along with β-catenin protein levels, was reduced in SCD1 knocked-down cells, and estrogen concentration was reduced (p < 0.05) in cell culture medium measured by enzyme-linked immunosorbent assay. SCD1 overexpression preserving β-catenin protein stability was evaluated by coimmunoprecipitation and Western blotting. The SCD1 inhibitor A939572, and a potential SCD1 inhibitor, grape seed extract (GSE), significantly inhibited cell migration and invasion by blocking SCD1 and its downstream β-catenin, CYP19A1 expression, and estrogen concentration. In vivo tumor formation assay and a tail vein metastasis model indicated that knockdown of SCD1 blocked tumor growth and metastasis. In conclusion, SCD1 could accelerate metastasis by maintaining the protein stability of β-catenin and then promoting CYP19A1 transcription to improve estrogen synthesis. SCD1 is expected to be a promised therapeutic target, and its novel inhibitor, GSE, has great therapeutic potential in NSCLC. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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13 pages, 15020 KiB

Open AccessArticle

Inhibition of Ribosomal RNA Processing 15 Homolog (RRP15) Suppressed Tumor Growth, Invasion and Epithelial to Mesenchymal Transition (EMT) of Colon Cancer

by Zirong Deng, Yun Xu, Yuchen Cai, Weiling Lin, Libei Zhang, Aoqing Jiang, Yuhang Zhou, Rui Zhao, Heyan Zhao, Zhaoguo Liu and Tingdong Yan

Int. J. Mol. Sci. 2023, 24(4), 3528; https://doi.org/10.3390/ijms24043528 - 9 Feb 2023

Cited by 2 | Viewed by 1532

Abstract

Although ribosomal RNA processing 15 Homolog (RRP15) has been implicated in the occurrence of various cancers and is considered a potential target for cancer treatment, its significance in colon cancer (CC) is unclear. Thus, this present study aims to determine RRP15 expression and [...] Read more.

Although ribosomal RNA processing 15 Homolog (RRP15) has been implicated in the occurrence of various cancers and is considered a potential target for cancer treatment, its significance in colon cancer (CC) is unclear. Thus, this present study aims to determine RRP15 expression and biological function in CC. The results demonstrated a strong expression of RRP15 in CC compared to normal colon specimens, which was correlated with poorer overall survival (OS) and disease-free survival (DFS) of the patients. Among the nine investigated CC cell lines, RRP15 demonstrated the highest and lowest expression in HCT15 and HCT116 cells, respectively. In vitro assays demonstrated that the knockdown of RRP15 inhibited the growth, colony-forming ability and invasive ability of the CC cells whereas its overexpression enhanced the above oncogenic function. Moreover, subcutaneous tumors in nude mice showed that RRP15 knockdown inhibited the CC growth while its overexpression enhanced their growth. Additionally, the knockdown of RRP15 inhibited the epithelial–mesenchymal transition (EMT), whereas overexpression of RRP15 promoted the EMT process in CC. Collectively, inhibition of RRP15 suppressed tumor growth, invasion and EMT of CC, and might be considered a promising therapeutic target for treating CC. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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18 pages, 10730 KiB

Open AccessArticle

ENO1 Promotes OSCC Migration and Invasion by Orchestrating IL-6 Secretion from Macrophages via a Positive Feedback Loop

by Ying Lin, Wenwen Zhang, Luyao Liu, Weibo Li, Yafei Li and Bo Li

Int. J. Mol. Sci. 2023, 24(1), 737; https://doi.org/10.3390/ijms24010737 - 1 Jan 2023

Cited by 6 | Viewed by 2523

Abstract

Oral squamous cell carcinoma (OSCC) has a five-year survival rate of less than 50% due to its susceptibility to invasion and metastasis. Crosstalk between tumor cells and macrophages has been proven to play a critical role in tumor cell migration and invasion. However, [...] Read more.

Oral squamous cell carcinoma (OSCC) has a five-year survival rate of less than 50% due to its susceptibility to invasion and metastasis. Crosstalk between tumor cells and macrophages has been proven to play a critical role in tumor cell migration and invasion. However, the specific mechanisms by which tumor cells interact with macrophages have not been fully elucidated. This study sought to investigate the regulatory mechanism of tumor cell-derived alpha-enolase (ENO1) in the interaction between tumor cells and macrophages during OSCC progression. Small interfering RNA (siRNA) transfection and recombinant human ENO1 (rhENO1) stimulation were used to interfere with the interaction between tumor cells and macrophages. Our results showed that ENO1 was expressed higher in CAL27 cells than in HaCaT cells and regulated lactic acid release in CAL27 cells. Conditioned medium of macrophages (Macro-CM) significantly up-regulated the ENO1 mRNA expression and protein secretion in CAL27 cells. ENO1 promoted the migration and invasion of tumor cells by facilitating the epithelial–mesenchymal transition (EMT) through macrophages. ENO1 orchestrated the IL-6 secretion of macrophages via tumor cell-derived lactic acid and the paracrine ENO1/Toll-like receptor (TLR4) signaling pathway. In turn, IL-6 promoted the migration and invasion of tumor cells. Collectively, ENO1 promotes tumor cell migration and invasion by orchestrating IL-6 secretion of macrophages via a dual mechanism, thus forming a positive feedback loop to promote OSCC progression. ENO1 might be a promising therapeutic target which is expected to control OSCC progression. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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14 pages, 3178 KiB

Open AccessArticle

Tumor Cell Capture Using Platelet-Based and Platelet-Mimicking Modified Human Serum Albumin Submicron Particles

by Xiaotong Zhao, Radostina Georgieva, Pichayut Rerkshanandana, Moritz Hackmann, Lara-Elena Heil Olaizola, Maxine Müller-de Ahna and Hans Bäumler

Int. J. Mol. Sci. 2022, 23(22), 14277; https://doi.org/10.3390/ijms232214277 - 18 Nov 2022

Cited by 2 | Viewed by 2480

Abstract

The co-localization of platelets and tumor cells in hematogenous metastases has long been recognized. Interactions between platelets and circulating tumor cells (CTCs) contribute to tumor cell survival and migration via the vasculature into other tissues. Taking advantage of the interactions between platelets and [...] Read more.

The co-localization of platelets and tumor cells in hematogenous metastases has long been recognized. Interactions between platelets and circulating tumor cells (CTCs) contribute to tumor cell survival and migration via the vasculature into other tissues. Taking advantage of the interactions between platelets and tumor cells, two schemes, direct and indirect, were proposed to target the modified human serum albumin submicron particles (HSA-MPs) towards tumor cells. HSA-MPs were constructed by the Co-precipitation–Crosslinking–Dissolution (CCD) method. The anti-CD41 antibody or CD62P protein was linked to the HSA-MPs separately via 1-ethyl-3-(-3-dimethyl aminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) EDC/NHS chemistry. The size of modified HSA-MPs was measured at approximately 1 µm, and the zeta potential was around −24 mV. Anti-CD41-HSA-MPs adhered to platelets as shown by flowcytometry and confocal laser scanning microscopy. In vitro, we confirmed the adhesion of platelets to tumor lung carcinoma cells A549 under shearing conditions. Higher cellular uptake of anti-CD41-HSA-MPs in A549 cells was found in the presence of activated platelets, suggesting that activated platelets can mediate the uptake of these particles. RNA-seq data in the Cancer Cell Lineage Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) database showed the expression of CD62P ligands in different types of cancers. Compared to the non-targeted system, CD62P-HSA-MPs were found to have higher cellular uptake in A549 cells. Our results suggest that the platelet-based and platelet-mimicking modified HSA-MPs could be promising options for tracking metastatic cancer. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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16 pages, 1885 KiB

Open AccessArticle

Evaluating the Safety and Quality of Life of Colorectal Cancer Patients Treated by Autologous Immune Enhancement Therapy (AIET) in Vinmec International Hospitals

by Hoang-Phuong Nguyen, Duc-Anh Dao Pham, Duy Dinh Nguyen, Phong Van Nguyen, Viet-Anh Bui, My-Nhung Thi Hoang and Liem Thanh Nguyen

Int. J. Mol. Sci. 2022, 23(19), 11362; https://doi.org/10.3390/ijms231911362 - 26 Sep 2022

Viewed by 4130

Abstract

(1) Colorectal cancer (CRC) is an increasingly prevalent disease with a high mortality rate in recent years. Immune cell-based therapies have received massive attention among scientists, as they have been proven effective as low-toxicity treatments. This study evaluated the safety and effectiveness of [...] Read more.

(1) Colorectal cancer (CRC) is an increasingly prevalent disease with a high mortality rate in recent years. Immune cell-based therapies have received massive attention among scientists, as they have been proven effective as low-toxicity treatments. This study evaluated the safety and effectiveness of autologous immune enhancement therapy (AIET) for CRC. (2) An open-label, single-group study, including twelve patients diagnosed with stages III and IV CRC, was conducted from January 2016 to December 2021. Twelve CRC patients received one to seven infusions of natural killer (NK)-cell and cytotoxic T-lymphocyte (CTL). Multivariate modelling was used to identify factors associated with health-related quality-of-life (HRQoL) scores. (3) After 20–21 days of culture, the NK cells increased 3535-fold, accounting for 85% of the cultured cell population. Likewise, CTLs accounted for 62.4% of the cultured cell population, which was a 1220-fold increase. Furthermore, the QoL improved with increased EORTC QLQ-C30 scores, decreased symptom severity, and reduced impairment in daily living caused by these symptoms (MDASI-GI report). Finally, a 14.3 ± 14.1-month increase in mean survival time was observed at study completion. (4) AIET demonstrated safety and improved survival time and HRQoL for CRC patients in Vietnam. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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16 pages, 3910 KiB

Open AccessArticle

Lamin-A/C Is Modulated by the Involvement of Histamine-Mediated Calcium/Calmodulin-Dependent Kinase II in Lung Cancer Cells

by Hyeong-Jae Kim, Peter C. W. Lee and Jeong Hee Hong

Int. J. Mol. Sci. 2022, 23(16), 9075; https://doi.org/10.3390/ijms23169075 - 13 Aug 2022

Cited by 4 | Viewed by 2471

Abstract

Lamins are nuclear envelope proteins involved in various cellular functions, such as DNA modulation, cellular differentiation, and development. In this study, we investigate the role of histamine in lung cancer biology. Since it is known that lamin-A/C is negatively regulated in lung cancer, [...] Read more.

Lamins are nuclear envelope proteins involved in various cellular functions, such as DNA modulation, cellular differentiation, and development. In this study, we investigate the role of histamine in lung cancer biology. Since it is known that lamin-A/C is negatively regulated in lung cancer, we hypothesize that histamine signaling is related to nuclear lamin-A/C regulation and cancer progression. Our findings reveal that histamine stimulation enhances lamin-A/C expression in lung cancer cells. Lamin-A/C expression is dependent on histamine-mediated intracellular calcium signaling and subsequent calcium/calmodulin-dependent kinase II (Ca/CaMKII) activation. The nuclear protein nestin, which stabilizes lamin-A/C expression, is also modulated by Ca/CaMKII. However, histamine-mediated lamin-A/C expression is independent of Akt/focal adhesion kinase or autophagy signaling. Histamine stimulation attenuates lung cancer motility in the presence of enhanced lamin-A/C expression. In conclusion, we propose a regulatory mechanism that accounts for the modulation of lamin-A/C levels through the involvement of Ca/CaMKII in cancer cells and provides molecular evidence of histamine signaling in lamin-A/C biology. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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16 pages, 5410 KiB

Open AccessArticle

Enhancement of Farnesoid X Receptor Inhibits Migration, Adhesion and Angiogenesis through Proteasome Degradation and VEGF Reduction in Bladder Cancers

by Chien-Rui Lai, Hisao-Hsien Wang, Hsin-Han Chang, Yu-Ling Tsai, Wen-Chiuan Tsai, Chen-Ray Lee, Chih-Ying Changchien, Yu-Chen Cheng, Sheng-Tang Wu and Ying Chen

Int. J. Mol. Sci. 2022, 23(9), 5259; https://doi.org/10.3390/ijms23095259 - 9 May 2022

Cited by 7 | Viewed by 2168

Abstract

(1) Background: Bladder cancer is a malignant tumor mainly caused by exposure to environmental chemicals, with a high recurrence rate. NR1H4, also known as Farnesoid X Receptor (FXR), acts as a nuclear receptor that can be activated by binding with bile acids, and [...] Read more.

(1) Background: Bladder cancer is a malignant tumor mainly caused by exposure to environmental chemicals, with a high recurrence rate. NR1H4, also known as Farnesoid X Receptor (FXR), acts as a nuclear receptor that can be activated by binding with bile acids, and FXR is highly correlated with the progression of cancers. The aim of this study was to verify the role of FXR in bladder cancer cells. (2) Methods: A FXR overexpressed system was established to investigate the effect of cell viability, migration, adhesion, and angiogenesis in low-grade TSGH8301 and high-grade T24 cells. (3) Results: After FXR overexpression, the ability of migration, adhesion, invasion and angiogenesis of bladder cancer cells declined significantly. Focal adhesive complex, MMP2, MMP9, and angiogenic-related proteins were decreased, while FXR was overexpressed in bladder cancer cells. Moreover, FXR overexpression reduced vascular endothelial growth factor mRNA and protein expression and secretion in bladder cancer cells. After treatment with the proteosome inhibitor MG132, the migration, adhesion and angiogenesis caused by FXR overexpression were all reversed in bladder cancer cells. (4) Conclusions: These results may provide evidence on the role of FXR in bladder cancer, and thus may improve the therapeutic efficacy of urothelial carcinoma in the future. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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Review

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23 pages, 3589 KiB

Open AccessReview

The Journey of Cancer Cells to the Brain: Challenges and Opportunities

by Marzena Łazarczyk, Michel Edwar Mickael, Dominik Skiba, Ewa Kurzejamska, Michał Ławiński, Jarosław Olav Horbańczuk, Jakub Radziszewski, Karolina Fraczek, Renata Wolinska, Justyna Paszkiewicz, Piotr Religa and Mariusz Sacharczuk

Int. J. Mol. Sci. 2023, 24(4), 3854; https://doi.org/10.3390/ijms24043854 - 14 Feb 2023

Cited by 5 | Viewed by 4700

Abstract

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of [...] Read more.

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood–brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood–brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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22 pages, 3971 KiB

Open AccessReview

NMDA Receptor and Its Emerging Role in Cancer

by Simona Gallo, Annapia Vitacolonna and Tiziana Crepaldi

Int. J. Mol. Sci. 2023, 24(3), 2540; https://doi.org/10.3390/ijms24032540 - 28 Jan 2023

Cited by 10 | Viewed by 6769

Abstract

Glutamate is a key player in excitatory neurotransmission in the central nervous system (CNS). The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel which presents several unique features and is involved in various physiological and pathological neuronal processes. Thanks to great efforts in [...] Read more.

Glutamate is a key player in excitatory neurotransmission in the central nervous system (CNS). The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel which presents several unique features and is involved in various physiological and pathological neuronal processes. Thanks to great efforts in neuroscience, its structure and the molecular mechanisms controlling its localization and functional regulation in neuronal cells are well known. The signaling mediated by NMDAR in neurons is very complex as it depends on its localization, composition, Ca²⁺ influx, and ion flow-independent conformational changes. Moreover, NMDA receptors are highly diffusive in the plasma membrane of neurons, where they form heterocomplexes with other membrane receptors and scaffold proteins which determine the receptor function and activation of downstream signaling. Interestingly, a recent paper demonstrates that NMDAR signaling is involved in epithelial cell competition, an evolutionary conserved cell fitness process influencing cancer initiation and progress. The idea that NMDAR signaling is limited to CNS has been challenged in the past two decades. A large body of evidence suggests that NMDAR is expressed in cancer cells outside the CNS and can respond to the autocrine/paracrine release of glutamate. In this review, we survey research on NMDAR signaling and regulation in neurons that can help illuminate its role in tumor biology. Finally, we will discuss existing data on the role of the glutamine/glutamate metabolism, the anticancer action of NMDAR antagonists in experimental models, NMDAR synaptic signaling in tumors, and clinical evidence in human cancer. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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14 pages, 1446 KiB

Open AccessReview

Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis

by Dongun Lee and Jeong-Hee Hong

Int. J. Mol. Sci. 2022, 23(24), 15475; https://doi.org/10.3390/ijms232415475 - 7 Dec 2022

Cited by 6 | Viewed by 2503

Abstract

PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been [...] Read more.

PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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17 pages, 2805 KiB

Open AccessReview

The Multifaceted Role of Signal Peptide-CUB-EGF Domain-Containing Protein (SCUBE) in Cancer

by Shashank Kumar, Kumari Sunita Prajapati and Sanjay Gupta

Int. J. Mol. Sci. 2022, 23(18), 10577; https://doi.org/10.3390/ijms231810577 - 12 Sep 2022

Cited by 5 | Viewed by 2685

Abstract

Signal peptide, CUB, and EGF-like domain-containing proteins (SCUBE) are secretory cell surface glycoproteins that play key roles in the developmental process. SCUBE proteins participate in the progression of several diseases, including cancer, and are recognized for their oncogenic and tumor suppressor functions depending [...] Read more.

Signal peptide, CUB, and EGF-like domain-containing proteins (SCUBE) are secretory cell surface glycoproteins that play key roles in the developmental process. SCUBE proteins participate in the progression of several diseases, including cancer, and are recognized for their oncogenic and tumor suppressor functions depending on the cellular context. SCUBE proteins promote cancer cell proliferation, angiogenesis, invasion, or metastasis, stemness or self-renewal, and drug resistance. The association of SCUBE with other proteins alters the expression of signaling pathways, including Hedgehog, Notch, TGF-β/Smad2/3, and β-catenin. Further, SCUBE proteins function as potential prognostic and diagnostic biomarkers for breast cancer, renal cell carcinoma, endometrial carcinoma, and nasopharyngeal carcinoma. This review presents key features of SCUBE family members, and their structure and functions, and highlights their contribution in the development and progression of cancer. A comprehensive understanding of the role of SCUBE family members offers novel strategies for cancer therapy. Full article

(This article belongs to the Special Issue A New Frontier on Cancer Invasion and Metastasis Research 2022)

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