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Fulltext Cancer stem cells as key drivers of tumour progression

Ayob AZ, Ramasamy TS

J Biomed Sci, 2018 Mar 06;25(1):20.
PMID: 29506506 DOI: 10.1186/s12929-018-0426-4

BACKGROUND: Cancer stem cells (CSCs) are subpopulations of cancer cells sharing similar characteristics as normal stem or progenitor cells such as self-renewal ability and multi-lineage differentiation to drive tumour growth and heterogeneity. Throughout the cancer progression, CSC can further be induced from differentiated cancer cells via the adaptation and cross-talks with the tumour microenvironment as well as a response from therapeutic pressures, therefore contributes to their heterogeneous phenotypes. Challengingly, conventional cancer treatments target the bulk of the tumour and are unable to target CSCs due to their highly resistance nature, leading to metastasis and tumour recurrence.
MAIN BODY: This review highlights the roles of CSCs in tumour initiation, progression and metastasis with a focus on the cellular and molecular regulators that influence their phenotypical changes and behaviours in the different stages of cancer progression. We delineate the cross-talks between CSCs with the tumour microenvironment that support their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation in response to therapeutic pressure. An insight into the distinct roles of CSCs in promoting angiogenesis and metastasis has been captured based on in vitro and in vivo evidences.
CONCLUSION: Given dynamic cellular events along the cancer progression and contributions of resistance nature by CSCs, understanding their molecular and cellular regulatory mechanism in a heterogeneous nature, provides significant cornerstone for the development of CSC-specific therapeutics.

Matched MeSH terms: Gene Expression Regulation, Neoplastic/physiology*
Gene expression in human oral squamous cell carcinoma is influenced by risk factor exposure

Cheong SC, Chandramouli GV, Saleh A, Zain RB, Lau SH, Sivakumaren S, et al.

Oral Oncol, 2009 Aug;45(8):712-9.
PMID: 19147396 DOI: 10.1016/j.oraloncology.2008.11.002

Oral squamous cell carcinoma (OSCC) is a world health problem and is associated with exposure to different risk factors. In the west, smoking and alcohol consumption are considered to be the main risk factors whilst in India and southeast Asia, betel quid (BQ) chewing is predominant. In this study, we compared the gene expression patterns of oral cancers associated with BQ chewing to those caused by smoking using Affymetrix microarrays. We found that 281 genes were differentially expressed between OSCC and normal oral mucosa regardless of aetiological factors including MMP1, PLAU, MAGE-D4, GNA12, IFITM3 and NMU. Further, we identified 168 genes that were differentially expressed between the BQ and smoking groups including CXCL-9, TMPRSS2, CA12 and RNF24. The expression of these genes was validated using qPCR using independent tissue samples. The results demonstrate that whilst common genes/pathways contribute to the development of oral cancer, there are also other gene expression changes that are specific to certain risk factors. The findings suggest that different carcinogens activate or inhibit specific pathways during cancer development and progression. These unique gene expression profiles should be taken into consideration when developing biomarkers for future use in prognostic or therapeutic applications.

Matched MeSH terms: Gene Expression Regulation, Neoplastic/physiology*
Fulltext Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

Ibrahim K, Abdul Murad NA, Harun R, Jamal R

Int J Mol Med, 2020 Aug;46(2):685-699.
PMID: 32468002 DOI: 10.3892/ijmm.2020.4619

Glioblastoma multiforme (GBM) is an aggressive type of brain tumour that commonly exhibits resistance to treatment. The tumour is highly heterogenous and complex kinomic alterations have been reported leading to dysregulation of signalling pathways. The present study aimed to investigate the novel kinome pathways and to identify potential therapeutic targets in GBM. Meta‑analysis using Oncomine identified 113 upregulated kinases in GBM. RNAi screening was performed on identified kinases using ON‑TARGETplus siRNA library on LN18 and U87MG. Tousled‑like kinase 1 (TLK1), which is a serine/threonine kinase was identified as a potential hit. In vitro functional validation was performed as the role of TLK1 in GBM is unknown. TLK1 knockdown in GBM cells significantly decreased cell viability, clonogenicity, proliferation and induced apoptosis. TLK1 knockdown also chemosensitised the GBM cells to the sublethal dose of temozolomide. The downstream pathways of TLK1 were examined using microarray analysis, which identified the involvement of DNA replication, cell cycle and focal adhesion signalling pathways. In vivo validation of the subcutaneous xenografts of stably transfected sh‑TLK1 U87MG cells demonstrated significantly decreased tumour growth in female BALB/c nude mice. Together, these results suggested that TLK1 may serve a role in GBM survival and may serve as a potential target for glioma.

Matched MeSH terms: Gene Expression Regulation, Neoplastic/physiology
Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma

Yap LF, Velapasamy S, Lee HM, Thavaraj S, Rajadurai P, Wei W, et al.

J Pathol, 2015 Feb;235(3):456-65.
PMID: 25294670 DOI: 10.1002/path.4460

Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease.

Matched MeSH terms: Gene Expression Regulation, Neoplastic/physiology*
Fulltext Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3

Lee HM, Lo KW, Wei W, Tsao SW, Chung GTY, Ibrahim MH, et al.

J Pathol, 2017 05;242(1):62-72.
PMID: 28240350 DOI: 10.1002/path.4879

Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration. We also show that S1P receptor 3 (S1PR3) mRNA is overexpressed in EBV-positive NPC patient-derived xenografts and a subset of primary NPC tissues, and that knockdown of S1PR3 suppressed the activation of AKT and the S1P-induced migration of NPC cells. Taken together, our data point to a central role for EBV in mediating the oncogenic effects of S1P in NPC and identify S1P signalling as a potential therapeutic target in this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Matched MeSH terms: Gene Expression Regulation, Neoplastic/physiology
Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells

Wu YS, Chung I, Wong WF, Masamune A, Sim MS, Looi CY

Biochim Biophys Acta Gen Subj, 2017 Feb;1861(2):296-306.
PMID: 27750041 DOI: 10.1016/j.bbagen.2016.10.006

BACKGROUND: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process.
METHODS: Gene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion.
RESULTS: PSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6.
CONCLUSIONS: IL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway.
GENERAL SIGNIFICANCE: Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.

Matched MeSH terms: Gene Expression Regulation, Neoplastic/physiology