Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.
Recent advances have found irregular activities of the nervous system-associated factors in the development and progression of primary liver cancer. These factors contributed in the regulation of migration, proliferation, and apoptosis of cancer cells, and took a role in modulating invasion, metastasis, and recurrence after curative treatment. In clinical researches, neural-related factors were found to be significant prognostic factors, suggesting that the interactions between nervous system and primary liver cancer are indispensable in understanding underlying biological mechanisms. Herein, we reviewed up-to-date achievements in this area and the future perspectives of the interactions between the nervous system and primary liver cancer.
Immune checkpoint blockade therapy targeting CTLA4 and PD-1/PD-L1 is a promising strategy in the treatment of different types of cancers. However, the clinical success rates of these therapies are still moderate and varied among cancer types. Therefore, identification of alternative and novel checkpoint molecules or interrupting tolerogenic pathways is urgently needed for successful tumor immunotherapy. Immunoglobulin-like transcript 4 (ILT4) is as an immunosuppressive molecule predominantly expressed in myeloid cells, including monocytes, macrophages, dendritic cells and granulocytes. Recent studies revealed that ILT4 is also enriched in tumor cells and stroma cells in the tumor microenvironment of various malignancies, modulating the biological behaviors of tumor cells and promoting their immune escape. However, the underlying mechanisms responsible for ILT4-mediated tumor development and progression are still poorly understood. In this review, we explore the functional role of ILT4 as a novel checkpoint molecule in cancers. We specifically discuss the mechanisms mediated by ILT4 for controlling tumor malignant behaviors, impairing effector anti-tumor immune responses, and sustaining the tumor suppressive microenvironment. We also highlight the potential role of ILT4 as a novel immune checkpoint target for tumor immunotherapy. Improved understanding of these issues is critical for elucidation of the role of ILT4 in tumor pathogenesis and should open new avenues for cancer immunotherapy specifically targeting this novel and alternative checkpoint molecule.
Protein restriction without malnutrition is currently an effective nutritional intervention known to prevent diseases and promote health span from yeast to human. Recently, low protein diets are reported to be associated with lowered cancer incidence and mortality risk of cancers in human. In murine models, protein restriction inhibits tumor growth via mTOR signaling pathway. IGF-1, amino acid metabolic programing, FGF21, and autophagy may also serve as potential mechanisms of protein restriction mediated cancer prevention. Together, dietary intervention aimed at reducing protein intake can be beneficial and has the potential to be widely adopted and effective in preventing and treating cancers.
Natural killer (NK) cells are an important subset of lymphocytes which play a critical role in host immunity against cancers. With MHC-independent recognition, short lifespan and potent cytotoxicity, NK cells make a promising candidate for chimeric antigen receptor (CAR)-engineered cancer immunotherapy. Due to innate biological properties of NK cells, CAR-NK may outperform CAR-T therapy in terms of less side effects and more universal access, which may become a great reformation in CAR-based cancer immunotherapy. The CARs used in peripheral blood (PB) NK cells as well as NK cell line like NK-92 are the most important outfits defining antigenic specificity. The constructs of CARs used in NK cells from different sources vary, which all undergo generational optimization. The anti-tumor effects of CAR-NK have been validated in numerous preclinical trials for cancers, including hematologic malignancies and many solid tumors, which provide evidence for potential clinical application of CAR-NK. Additionally, this review concludes the challenges faced in the application of CAR-NK. Although CAR-NK is considered as one of the most possible "off-the-shelf" products, the improvement for the efficiency of expansion and transduction as well as the solution for underlying safety issues is still needed. Possible coping strategies for challenges and upgrades in techniques are also highlighted for future development in CAR-NK cancer immunotherapy.
The driving roles of fusion genes during tumorigenesis have been recognized for decades, with efficacies demonstrated in clinical diagnosis and targeted therapy. With advances in sequencing technologies and computational biology, a surge in the identification of fusion genes has been witnessed during the past decade. The discovery and presence of splicing based fusions in normal tissues have challenged our canonical conceptions on fusion genes and offered us novel medical opportunities. The specificity of fusion genes to neoplastic tissues and their diverse functionalities during carcinogenesis foster them as promising tools in the battle against cancer. It is time to re-visit and comb through our cutting-edge knowledge on fusion genes to accelerate clinical translation of these internal markers. Urged as such, we are encouraged to categorize fusion events according to mechanisms leading to their generation, oncological consequences and clinical implications, offer insights on fusion occurrence across tumors from the system level, highlight feasible practices in fusion-related pharmaceutical development, and identify understudied yet important niches that may lead future research trend in this field.
Hepatocellular carcinoma (HCC) is the commonest primary liver cancer and the second leading cause of cancer death worldwide. Obesity is rapidly becoming pandemic and associated with increased carcinogenesis. In this review, we describe the obesity-related factors that influence the development of HCC. We provide evidence of strong links between neural regulation, endocrine and HCC in obesity. We discuss recent advances in our understanding of how adipose tissue alters hepatic metabolism and immune response in HCC development through inter-organ communication. Taken together, our review aims to provides a concise and up-to date summary about the connection between obesity and HCC, with emphasis on the opportunities for effective strategies in preventing the development of HCC in obese individuals.
Over half of patients with diffuse large B-cell lymphoma (DLBCL) can be cured by standard R-CHOP treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). However, the remaining patients are refractory and ultimately succumb to progressive or relapsed disease. During the past decade, there has been significant progress in the understanding of molecular mechanisms in DLBCL, largely owing to collaborative efforts in large-scale gene expression profiling and deep sequencing, which have identified genetic alterations critical in lymphomagenesis through activation of key signaling transduction pathways in DLBCL. These discoveries have not only led to the development of targeted therapies, including several currently in clinical trials, but also laid a solid foundation for the future identification of more effective therapies for patients not curable by R-CHOP. This review summarizes the recent advances in our understanding of the molecular characterization and pathogenesis of DLBCL and new treatment directions.
Androgen receptor (AR) targeted treatment has shown promising preliminary results in triple negative breast cancer (TNBC). Identification of AR-associated signaling pathways is of great significance for in-depth understanding of their roles in pathogenesis of TNBC. To meet this objective, preclinical and clinical studies were conducted to clarify the biological interactions of AR signaling and combination strategies based on AR-targeted therapy. Biologically, AR signaling in TNBC which not only interacts with a network of key pathways, involving PI3K/AKT/mTOR, cell cycle, and DNA damage repair pathways, but mediates pivotal processes of tumor initiation and immunogenic modulation, may present an opportunity to overcome the insensitivity of single AR targeted therapy. Research in investigating androgen-blockade based combination therapy in this aggressive tumor has demonstrated promising benefit in preclinical studies, and comparable clinical trials of combined strategies with CDK4/6 inhibitors, PI3K inhibition, chemotherapy, and immunotherapy, are ongoing. Accordingly, clinical interpretation of AR-related biological interactions, aiming at combined blockade of the signaling pathways may pave a new way for endocrine-based therapy in the treatment of TNBC.
Circular RNA (circRNA), a recently discovered subclass of non-coding RNAs (ncRNAs), forms a covalently closed loop with neither a 5' cap structure nor a 3' polyadenylated tail. Generated from precursor mRNA (pre-mRNA) through "backsplicing" (a type of alternative RNA splicing), the majority of circRNAs are located in the cytoplasm and are widespread among living organisms. They are stable and conserved and exhibit spatiotemporal-specific expression. CircRNAs are known to be involved in the development and progression of multiple diseases, including cancer, by acting as microRNA (miRNA) sponges and by regulating processes such as transcription and translation. The extensively aberrant expression profiles of circRNAs in multiple cancerous tissues make these molecules promising diagnostic biomarkers and therapeutic targets for cancer. Here, we briefly review the characteristics, biogenesis, classification, and functions of circRNAs, with a particular focus on the role of circRNAs in various cancers.
While metabolic reprogramming of cancer cells has long been considered from the standpoint of how and why cancer cells preferentially utilize glucose via aerobic glycolysis, the so-called Warburg Effect, the progress in the following areas during the past several years has substantially advanced our understanding of the rewired metabolic network in cancer cells that is intertwined with oncogenic signaling. First, in addition to the major nutrient substrates glucose and glutamine, cancer cells have been discovered to utilize a variety of unconventional nutrient sources for survival. Second, the deregulated biomass synthesis is intertwined with cell cycle progression to coordinate the accelerated progression of cancer cells. Third, the reciprocal regulation of cancer cell's metabolic alterations and the microenvironment, involving extensive host immune cells and microbiota, have come into view as critical mechanisms to regulate cancer progression. These and other advances are shaping the current and future paradigm of cancer metabolism.
Cell division is a tightly-regulated process that involves the contribution of a large number of proteins. Before they are able to undergo mitosis, cells must first synthesize new DNA, effectively and accurately duplicating their genome. This occurs during what is called the S-phase and requires a fine control in order to avoid replication errors. The synthesis of new DNA takes place in the origin, specific locations in the genome where the double strands of DNA are unwound and separated, allowing for the binding of proteins and complexes that will build new strands of the genomic material, using the existing ones as molds, in what is referred to as semi-conservative process. While the overall flow of the DNA synthesis process has been elucidated, its regulation and the exact role of its contributors are not yet entirely understood. It is believed that the Minichromosome Maintenance (MCM) proteins occupy a central role in DNA synthesis. Given their contribution to a central aspect in the conservation of life, further studies have been launched to understand how the MCM proteins may affect or be affected by pathologies involving cell division, such as neoplasia. In this review, we aim to give an overview on the members of the MCM family, what their functions are in a healthy environment and how they are altered in cancer.
Protein kinase D is a family of evolutionarily conserved serine/threonine kinases that belongs to the Ca++/Calmodulin-dependent kinase superfamily. Signal transduction pathways mediated by PKD can be triggered by a variety of stimuli including G protein-coupled receptor agonists, growth factors, hormones, and cellular stresses. The regulatory mechanisms and physiological roles of PKD have been well documented including cell proliferation, survival, migration, angiogenesis, regulation of gene expression, and protein/membrane trafficking. However, its precise roles in disease progression, especially in cancer, remain elusive. A plethora of studies documented the cell- and tissue-specific expressions and functions of PKD in various cancer-associated biological processes, while the causes of the differential effects of PKD have not been thoroughly investigated. In this review, we have discussed the structural-functional properties, activation mechanisms, signaling pathways and physiological functions of PKD in the context of human cancer. Additionally, we have provided a comprehensive review of the reported tumor promoting or tumor suppressive functions of PKD in several major cancer types and discussed the discrepancies that have been raised on PKD as a major regulator of malignant transformation.
It is disappointing that only a few patients with hepatocellular carcinoma (HCC) obtain a significant survival benefit from the sorafenib treatment, which is currently regarded as a first-line chemotherapeutic therapy in patients with advanced HCC. Most patients are highly refractory to this therapy. Therefore, it is necessary to identify resistant factors and explore potential protocols that can be used to overcome the resistance or substitute sorafenib once the resistance is formed. In fact, a growing body of studies has been focusing on the resistance mechanisms or the method to overcome it. The limitation of sorafenib efficacy has been partially but not fully elucidated. Moreover, some protocols have shown encouraging outcomes but still need to be further verified in clinical trials. In this review, we summarize the recent findings on the potential mechanisms that contribute to sorafenib resistance and discuss strategies that can be used to improve the treatment outcome.
Metabolism is essential to all living organisms that provide cells with energy, regulators, building blocks, enzyme cofactors and signaling molecules, and is in tune with nutritional conditions and the function of cells to make the appropriate developmental decisions or maintain homeostasis. As a fundamental biological process, metabolism state affects the production of multiple metabolites and the activation of various enzymes that participate in regulating gene expression, cell apoptosis, cancer progression and immunoreactions. Previous studies generally focus on the function played by the metabolic enzymes in the cytoplasm and mitochondrion. In this review, we conclude the role of them in the nucleus and their implications for cancer progression, immunity and metastasis.