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Protective role of LRRC3B in preventing breast cancer metastasis and recurrence post-bupivacaine.

ABSTRACT: The present study aimed to investigate the potential effect of leucine-rich repeat containing 3B (LRRC3B) with respect to the inhibition of breast cancer recurrence and metastasis post-anesthesia. The mRNA expression of LRRC3B in breast MDA-MB-231 and MCF-7 cell lines was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The effect of bupivacaine on breast cancer cell invasion was analyzed using a Matrigel assay. LRRC3B specific small interfering (si)RNA was constructed and transfected into breast cancer cells using Lipofectamine® 2000 reagent. The influence of bupivacaine on LRRC3B expression was measured based on RT-qPCR. Additionally, the effect of LRRC3B silencing on the invasion of breast cancer cells treated with bupivacaine was analyzed. Compared with the control, LRRC3B expression significantly increased in MDA-MB-231 and in MCF-7 cells as the length of time increased (P<0.05), but the expression of the gene significantly declined in 2 types of cancer cell when the cells were transfected with siRNA-LRRC3B plasma (P<0.05). The administration of 50 µg/ml bupivacaine promoted maximum breast cancer cell invasion, and suppressed LRRC3B mRNA expression in cells. However, when LRRC3B was silenced in cancer cells, 20 µg/ml bupivacaine significantly promoted cancer cell invasion, indicating that bupivacaine suppresses the expression of LRRC3B and promotes cell invasion. The present study suggested that LRRC3B serves a protective role in preventing bupivacaine-induced breast cancer recurrence and metastasis.

SUBMITTER: Li GS

PROVIDER: S-EPMC5649644 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Protective role of LRRC3B in preventing breast cancer metastasis and recurrence post-bupivacaine.

Li Gong-Sheng GS Kong Gao-Yin GY Zou Yi Y

Oncology letters 20170818 4

The present study aimed to investigate the potential effect of leucine-rich repeat containing 3B (LRRC3B) with respect to the inhibition of breast cancer recurrence and metastasis post-anesthesia. The mRNA expression of LRRC3B in breast MDA-MB-231 and MCF-7 cell lines was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The effect of bupivacaine on breast cancer cell invasion was analyzed using a Matrigel assay. LRRC3B specific small interfering (si ...[more]

PMID: 29085514

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Project description:BackgroundSeaweed polysaccharides have been recommended as anticancer supplements and for boosting human health; however, their benefits in the treatment of triple-negative breast cancers (TNBCs) and improving immune surveillance remain unclear. Olaparib is a first-in-class poly (ADP-ribose) polymerase inhibitor. Oligo-Fucoidan, a low-molecular-weight sulfated polysaccharide purified from brown seaweed (Laminaria japonica), exhibits significant bioactivities that may aid in disease management.MethodsMacrophage polarity, clonogenic assays, cancer stemness properties, cancer cell trajectory, glucose metabolism, the TNBC 4T1 cells and a 4T1 syngeneic mouse model were used to inspect the therapeutic effects of olaparib and Oligo-Fucoidan supplementation on TNBC aggressiveness and microenvironment.ResultsOlaparib treatment increased sub-G1 cell death and G2/M arrest in TNBC cells, and these effects were enhanced when Oligo-Fucoidan was added to treat the TNBC cells. The levels of Rad51 and programmed death-ligand 1 (PD-L1) and the activation of epidermal growth factor receptor (EGFR) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) facilitate drug resistance and TNBC metastasis. However, the combination of olaparib and Oligo-Fucoidan synergistically reduced Rad51 and PD-L1 levels, as well as the activity of EGFR and AMPK; consistently, TNBC cytotoxicity and stemness were inhibited. Oligo-Fucoidan plus olaparib better inhibited the formation of TNBC stem cell mammospheroids with decreased subpopulations of CD44high/CD24low and EpCAMhigh cells than monotherapy. Importantly, Oligo-Fucoidan plus olaparib repressed the oncogenic interleukin-6 (IL-6)/p-EGFR/PD-L1 pathway, glucose uptake and lactate production. Oligo-Fucoidan induced immunoactive and antitumoral M1 macrophages and attenuated the side effects of olaparib, such as the promotion on immunosuppressive and protumoral M2 macrophages. Furthermore, olaparib plus Oligo-Fucoidan dramatically suppressed M2 macrophage invasiveness and repolarized M2 to the M0-like (F4/80high) and M1-like (CD80high and CD86high) phenotypes. In addition, olaparib- and Oligo-Fucoidan-pretreated TNBC cells resulted in the polarization of M0 macrophages into CD80(+) M1 but not CD163(+) M2 macrophages. Importantly, olaparib supplemented with oral administration of Oligo-Fucoidan in mice inhibited postsurgical TNBC recurrence and metastasis with increased cytotoxic T cells in the lymphatic system and decreased regulatory T cells and M2 macrophages in tumors.ConclusionOlaparib supplemented with natural compound Oligo-Fucoidan is a novel therapeutic strategy for reprogramming cancer stemness, metabolism and the microenvironment to prevent local postsurgical recurrence and distant metastasis. The combination therapy may advance therapeutic efficacy that prevent metastasis, chemoresistance and mortality in TNBC patients.

Project description:Epidemiological, clinical, and experimental data indicate that the risk of developing breast cancer is strongly dependent on the ovary and on endocrine conditions modulated by ovarian function, such as early menarche, late menopause, and parity. Women who gave birth to a child when they were younger than 24 years of age exhibit a decrease in their lifetime risk of developing breast cancer, and additional pregnancies increase the protection. The breast tissue of normally cycling women contains three identifiable types of lobules, the undifferentiated Lobules type 1 (Lob 1) and the more developed Lobules type 2 and Lobules type 3. The breast attains its maximum development during pregnancy and lactation (Lobules type 4). After menopause the breast regresses in both nulliparous and parous women containing only Lob 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women indicates that Lob 1 in these two groups of women might be biologically different, or might exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that Lob 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and are therefore susceptible to undergo neoplastic transformation. These epithelial cells are called Stem cells 1, whereas Lob 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the contrary, are composed of an epithelial cell population that is refractory to transformation, called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the 'genomic signature' that differentiates Lob 1 of the early parous women from that of the nulliparous women by shifting the Stem cells 1 to Stem cells 2 that are refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full-term pregnancy. The identification of a putative breast stem cell (Stem cells 1) has, in the past decade, reached a significant impulse, and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although further work needs to be carried out in order to better understand the role of the Stem cells 2 and their interaction with the genes that confer them a specific signature, collectively the data presently available provide evidence that pregnancy, through the process of cell differentiation, shifts Stem cells 1 to Stem cells 2 - cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis.

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Protective role of LRRC3B in preventing breast cancer metastasis and recurrence post-bupivacaine.

Publications

Protective role of LRRC3B in preventing breast cancer metastasis and recurrence post-bupivacaine.

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