Stem cell profiling in head and neck cancer reveals an Oct-4 expressing subpopulation with properties of chemoresistance

Reers, Stefan; Pfannerstill, Ann-Christin; Maushagen, Regina; Pries, Ralph; Wollenberg, Barbara

doi:10.1016/j.oraloncology.2013.12.006

Cited by 29 publications

(19 citation statements)

References 45 publications

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“…CD133, CD24, CD44, EPCAM and CXCR4 are known pancreatic cancer stem cell markers (36–38). OCT4 has been established as a stem cell marker in head and neck cancer (39). We observed that orlistat treatment significantly decreased the mRNA levels of these stemness markers in a panel of pancreatic cancer cell lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

et al. 2017

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Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single agent therapy for pancreatic cancer. While the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging TCGA dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of ER stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness.

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Section: Resultsmentioning

confidence: 99%

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

et al. 2017

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“…Overexpression of Oct4 has previously been implicated with chemoresistance in tumours [ 57 ]. Here we demonstrate significant elevation of Oct4A expression in established EOC cells which survived cisplatin treatment.…”

Section: Discussionmentioning

confidence: 99%

A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer

et al. 2015

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BackgroundHigh grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance.MethodsTo investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice.ResultsWe demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells.ConclusionsThis data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0417-y) contains supplementary material, which is available to authorized users.

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“…OCT4 is an essential transcription factor of embryonic development, involving maintenance of the pluripotency and self-renewal of embryonic stem cells (ESCs) (1-3), and is a main factor in iPS cell generation (4-6). OCT4 is expressed in several types of cancer facilitating the maintenance of cancer stem cell (CSCs) properties (7)(8)(9)(10), and is associated with the degree of malignancy and the drug-resistance character of cancer (11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

OCT4B modulates OCT4A expression as ceRNA in tumor cells

Liu

Yang

et al. 2015

Oncology Reports

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OCT4 is an essential transcription factor for maintaining the self-renewal and the pluripotency of embryonic stem cells (ESCs). The human OCT4 gene can generate three mRNA isoforms (OCT4A, OCT4B and OCT4B1) by alternative splicing. OCT4A protein is a transcription factor for the stemness of ESCs, while the function of OCT4B isoforms remains unclear. Most types of cancer express a relatively low level of OCT4 protein, particularly the OCT4B isoforms. In the present study, we found that OCT4A and OCT4B mRNA were co-expressed in several types of tumor cell lines and tumor samples, and we demonstrated that OCT4B functioned as a non-coding RNA, modulating OCT4A expression in an miRNA-dependent manner [competing endogenous RNA (ceRNA) regulation] at the post-transcription level in the tumor cell lines. This is the first time that ceRNA regulation was observed among spliced isoforms of one gene, and may pave the way for identification of new targets for cancer treatment.

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Stem cell profiling in head and neck cancer reveals an Oct-4 expressing subpopulation with properties of chemoresistance

Cited by 29 publications

References 45 publications

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer

OCT4B modulates OCT4A expression as ceRNA in tumor cells

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