SALL Proteins; Common and Antagonistic Roles in Cancer

SALL proteins are a family of four conserved C2H2 zinc finger transcription factors that play critical roles in organogenesis during embryonic development. They regulate cell proliferation, survival, migration, and stemness; consequently, they are involved in various human genetic disorders and cancer. SALL4 is a well-recognized oncogene; however, SALL1–3 play dual roles depending on the cancer context and stage of the disease. Current reviews of SALLs have focused only on SALL2 or SALL4, lacking an integrated view of the SALL family members in cancer. Here, we update the recent advances of the SALL members in tumor development, cancer progression, and therapy, highlighting the synergistic and/or antagonistic functions they perform in similar cancer contexts. We identified common regulatory mechanisms, targets, and signaling pathways in breast, brain, liver, colon, blood, and HPV-related cancers. In addition, we discuss the potential of the SALL family members as cancer biomarkers and in the cancer cells’ response to therapies. Understanding SALL proteins’ function and relationship will open new cancer biology, clinical research, and therapy perspectives.

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The Roles of Sirtuin Family Proteins in Cancer Progression

Cancers ◽

10.3390/cancers11121949 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1949 ◽

Cited By ~ 8

Author(s):

Erhu Zhao ◽

Jianbing Hou ◽

Xiaoxue Ke ◽

Muhammad Nadeem Abbas ◽

Saima Kausar ◽

...

Keyword(s):

Cancer Progression ◽

Tumor Suppressors ◽

Family Members ◽

Critical Discussion ◽

Biological Pathways ◽

Tumor Promoters ◽

Malignant Phenotype ◽

Dual Roles ◽

Adp Ribosyltransferase ◽

High Degree

Sirtuin family members are characterized by either mono-ADP-ribosyltransferase or deacylase activity and are linked to various cancer-related biological pathways as regulators of transcriptional progression. Sirtuins play fundamental roles in carcinogenesis and maintenance of the malignant phenotype, mainly participating in cancer cell viability, apoptosis, metastasis, and tumorigenesis. Although sirtuin family members have a high degree of homology, they may play different roles in various kinds of cancer. This review highlights their fundamental roles in tumorigenesis and cancer development and provides a critical discussion of their dual roles in cancer, namely, as tumor promoters or tumor suppressors.

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Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation

International Journal of Molecular Sciences ◽

10.3390/ijms21165744 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5744 ◽

Cited By ~ 8

Author(s):

Yoshihisa Tokumaru ◽

Masanori Oshi ◽

Eriko Katsuta ◽

Li Yan ◽

Jing Li Huang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Cancer Biology ◽

The Cancer Genome Atlas ◽

Related Gene ◽

Immune Microenvironment ◽

Gene Sets ◽

Tumor Immune Microenvironment ◽

Er Positive

Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as “intratumoral adipocyte”. These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.

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Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

The International Journal of Biological Markers ◽

10.1177/1724600820906155 ◽

2020 ◽

Vol 35 (1_suppl) ◽

pp. 8-11 ◽

Cited By ~ 3

Author(s):

Paola Nisticò ◽

Gennaro Ciliberto

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Tumor Development ◽

Short Paper ◽

Great Relevance ◽

Cellular Components ◽

The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

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The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13174443 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4443

Author(s):

Ankit Patel ◽

Masanori Oshi ◽

Li Yan ◽

Ryusei Matsuyama ◽

Itaru Endo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Unfolded Protein Response ◽

Cancer Progression ◽

Cancer Biology ◽

Immune Cell ◽

Histological Grade ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.

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Long non-coding RNA AFAP1-AS1 facilitates ovarian cancer progression by regulating the miR-107/PDK4 axis

Journal of Ovarian Research ◽

10.1186/s13048-021-00808-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Bao Liu ◽

Li Yan ◽

Yugang Chi ◽

Yuhan Sun ◽

Xiaoyu Yang

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Tumor Development ◽

Figo Stage ◽

Pyruvate Dehydrogenase Kinase ◽

Cell Counting ◽

Migration And Invasion ◽

Expression Levels ◽

Gene Reporter Assay

Abstract Background Abnormally expressed in various tumors, long non-coding RNAs (lncRNAs) feature prominently in tumor development, yet little is still known regarding the functional roles of lncRNA AFAP1 antisense RNA 1 (AFAP1-AS1) in ovarian cancer (OC). Methods The relative expression levels of lncRNA AFAP1-AS1, microRNA (miR)-107 and pyruvate dehydrogenase kinase isozyme 4 (PDK4) mRNA were assessed by quantitative real-time PCR. PDK4, PCNA and cyclin D1 expression levels were determined using Western blot analysis. Bioinformatics analysis and dual-luciferase gene reporter assay were conducted for identifying and validating the binding sequences between AFAP1-AS1 and miR-107, as well as between miR-107 and PDK4. Cell counting kit-8 assay was employed for detecting cell proliferation. Cell migration and invasion abilities were examined using Transwell assays. Results The present study revealed that AFAP1-AS1 expression was elevated in OC cells and tissues. AFAP1-AS1 expression and FIGO stage were positively correlated. AFAP1-AS1 knockdown repressed OC cell proliferation, migration and invasion. AFAP1-AS1 functioned as a sponge of miR-107, and miR-107 reversed the effects of AFAP1-AS1 on OC cells. It was validated that miR-107 was able to bind to PDK4, and AFAP1-AS1 regulated PDK4 expression by competitively binding with miR-107. Additionally, miR-107 modulated OC cell proliferation, migration and invasion via targeting PDK4. Conclusions LncRNA AFAP1-AS1 serves as a tumor driver in the pathogenesis of OC via the miR-107/PDK4 axis.

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Role of the Hsp90-Immunophilin Heterocomplex in Cancer Biology

Current Cancer Therapy Reviews ◽

10.2174/1573394715666190102120801 ◽

2020 ◽

Vol 16 (1) ◽

pp. 19-28

Author(s):

Sonia A. De Leo ◽

Nadia R. Zgajnar ◽

Gisela I. Mazaira ◽

Alejandra G. Erlejman ◽

Mario D. Galigniana

Keyword(s):

Cancer Progression ◽

Cancer Biology ◽

Steroid Receptors ◽

Human Cancer ◽

Tumor Development ◽

Biological Properties ◽

Tetratricopeptide Repeats ◽

Cellular Processes ◽

Client Factors ◽

Cancer Tissues

The identification of new factors that may function as cancer markers and become eventual pharmacologic targets is a challenge that may influence the management of tumor development and management. Recent discoveries connecting Hsp90-binding immunophilins with the regulation of signalling events that can modulate cancer progression transform this family of proteins in potential unconventional factors that may impact on the screening and diagnosis of malignant diseases. Immunophilins are molecular chaperones that group a family of intracellular receptors for immunosuppressive compounds. A subfamily of the immunophilin family is characterized by showing structural tetratricopeptide repeats, protein domains that are able to interact with the C-terminal end of the molecular chaperone Hsp90, and via the proper Hsp90-immunophilin complex, the biological properties of a number of client-proteins involved in cancer biology are modulated. Recent discoveries have demonstrated that two of the most studied members of this Hsp90- binding subfamily of immunophilins, FKBP51 and FKBP52, participate in several cellular processes such as apoptosis, carcinogenesis progression, and chemoresistance. While the expression levels of some members of the immunophilin family are affected in both cancer cell lines and human cancer tissues compared to normal samples, novel regulatory mechanisms have emerged during the last few years for several client-factors of immunophilins that are major players in cancer development and progression, among them steroid receptors, the transctiption factor NF-κB and the catalytic subunit of telomerase, hTERT. In this review, recent findings related to the biological properties of both iconic Hsp90-binding immunophilins, FKBP51 and FKBP52, are reviewed within the context of their interactions with those chaperoned client-factors. The potential roles of both immunophilins as potential cancer biomarkers and non-conventional pharmacologic targets for cancer treatment are discussed.

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Early and multiple origins of metastatic lineages within primary tumors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525677113 ◽

2016 ◽

Vol 113 (8) ◽

pp. 2140-2145 ◽

Cited By ~ 84

Author(s):

Zi-Ming Zhao ◽

Bixiao Zhao ◽

Yalai Bai ◽

Atila Iamarino ◽

Stephen G. Gaffney ◽

...

Keyword(s):

Cancer Progression ◽

Cancer Biology ◽

Tumor Development ◽

Evolutionary Process ◽

Driver Mutations ◽

Cancer Evolution ◽

Driver Genes ◽

Genetic Changes ◽

Primary Tumors ◽

Multiple Origins

Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases.

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Dual Roles of IL-27 in Cancer Biology and Immunotherapy

Mediators of Inflammation ◽

10.1155/2017/3958069 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 35

Author(s):

Marina Fabbi ◽

Grazia Carbotti ◽

Silvano Ferrini

Keyword(s):

Cell Proliferation ◽

Cancer Biology ◽

Cytotoxic T Lymphocyte ◽

Biological Activities ◽

Experimental Models ◽

Dual Roles ◽

Angiogenic Potential ◽

Potential Applications ◽

Regulatory Functions ◽

Acting In Concert

IL-27 is a pleiotropic two-chain cytokine, composed of EBI3 and IL-27p28 subunits, which is structurally related to both IL-12 and IL-6 cytokine families. IL-27 acts through a heterodimer receptor consisting of IL-27Rα(WSX1) and gp130 chains, which mediate signaling predominantly through STAT1 and STAT3. IL-27 was initially reported as an immune-enhancing cytokine that supports CD4+T cell proliferation, T helper (Th)1 cell differentiation, and IFN-γproduction, acting in concert with IL-12. However, subsequent studies demonstrated that IL-27 displays complex immune-regulatory functions, which may result in either proinflammatory or anti-inflammatory effects in relationship to the biological context and experimental models considered. Several pieces of evidence, obtained in preclinical tumor models, indicated that IL-27 has a potent antitumor activity, related not only to the induction of tumor-specific Th1 and cytotoxic T lymphocyte (CTL) responses but also to direct inhibitory effects on tumor cell proliferation, survival, invasiveness, and angiogenic potential. Nonetheless, given its immune-regulatory functions, the effects of IL-27 on cancer may be dual and protumor effects may also occur. Here, we will summarize IL-27 biological activities and its functional overlaps with the IFNs and discuss its dual role in tumors in the light of potential applications to cancer immunotherapy.

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Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01894-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xiaoxiao Zhou ◽

Kun Liu ◽

Jing Cui ◽

Jiongxin Xiong ◽

Heshui Wu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Cell Apoptosis ◽

Tumor Development ◽

Circular Rna ◽

Tumor Formation ◽

Luciferase Reporter ◽

Invasion And Migration

Abstract Background Pancreatic cancer is a malignant tumor and ranks the sixth in incidence among cancers. Circular RNA (circRNA) has been reported to regulate the progression of pancreatic cancer. However, the effects of circ-membrane bound O-acyltransferase domain containing 2 (circ-MBOAT2) on regulating pancreatic cancer process were unclear. Methods The expression levels of circ-MBOAT2, microRNA-433-3p (miR-433-3p) and glutamic-oxaloacetic transaminase 1 (GOT1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). GOT1 protein expression was determined by western blot analysis. Cell proliferation was illustrated by 3-(4,5)-dimethylthiahiazo (−z-y1)-3,5-di-phenytetrazoliumromide (MTT) and cell colony formation assay. Cell apoptosis was demonstrated by flow cytometry analysis. Cell invasion and migration were investigated by transwell invasion and wound-healing assays. Glutamine catabolism was explained by detecting glutamine consumption, alpha ketoglutarate (α-KG) production and glutamate production. In vivo assay was performed to illustrate the impacts of circ-MBOAT2 silencing on tumor formation in vivo. The binding relationship between miR-433-3p and circ-MBOAT2 or GOT1 was predicted by circinteractome or starbase online databases, and identified by dual-luciferase reporter assay. Results Circ-MBOAT2 and GOT1 expression were significantly upregulated, while miR-433-3p expression was downregulated in pancreatic cancer tissues and cells compared with normal pancreatic tissues or cells. Circ-MBOAT2 silencing repressed cell proliferation, migration, invasion and glutamine catabolism, whereas promoted cell apoptosis in pancreatic cancer. Additionally, circ-MBOAT2 acted as a sponge of miR-433-3p, which was found to be associate with GOT1. MiR-433-3p inhibitors hindered circ-MBOAT2 silencing-mediated impacts on pancreatic cancer progression and glutamine catabolism. Furthermore, circ-MBOAT2 silencing repressed tumor formation in vivo. Conclusion Circ-MBOAT2 modulated tumor development and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. This finding suggests that circ-MBOAT2 may be a therapeutic target for pancreatic cancer.

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Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer

Disease Markers ◽

10.1155/2016/2138627 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 15

Author(s):

Ángela Marrugal ◽

Laura Ojeda ◽

Luis Paz-Ares ◽

Sonia Molina-Pinelo ◽

Irene Ferrer

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Tumor Development ◽

Therapeutic Targets ◽

Cancer Biomarkers ◽

Invasion And Metastasis ◽

Inflammatory Processes ◽

New Biomarkers ◽

Cell Signaling Pathways ◽

Proteomic Techniques

Proteomic techniques are currently used to understand the biology of different human diseases, including studies of the cell signaling pathways implicated in cancer progression, which is important in knowing the roles of different proteins in tumor development. Due to its poor prognosis, proteomic approaches are focused on the identification of new biomarkers for the early diagnosis, prognosis, and targeted treatment of lung cancer. Cytokines are proteins involved in inflammatory processes and have been proposed as lung cancer biomarkers and therapeutic targets because it has been reported that some cytokines play important roles in tumor development, invasion, and metastasis. In this review, we aim to summarize the different proteomic techniques used to discover new lung cancer biomarkers and therapeutic targets. Several cytokines have been identified as important players in lung cancer using these techniques. We underline the most important cytokines that are useful as biomarkers and therapeutic targets. We also summarize some of the therapeutic strategies targeted for these cytokines in lung cancer.

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