Drug resistance in breast cancer is based on the mechanism of exocrine non-coding RNA.

Breast cancer (BC) ranks first among female malignant tumors and involves hormonal changes and genetic as well as environmental risk factors. In recent years, with the improvement of medical treatment, a variety of therapeutic approaches for breast cancer have emerged and have strengthened to accommodate molecular diversity. However, the primary way to improve the effective treatment of breast cancer patients is to overcome treatment resistance. Recent studies have provided insights into the mechanisms of resistance to exosome effects in BC. Exosomes are membrane-bound vesicles secreted by both healthy and malignant cells that facilitate intercellular communication. Specifically, exosomes released by tumor cells transport their contents to recipient cells, altering their properties and promoting oncogenic components, ultimately resulting in drug resistance. As important coordinators, non-coding RNAs (ncRNAs) are involved in this process and are aberrantly expressed in various human cancers. Exosome-derived ncRNAs, including microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as crucial components in understanding drug resistance in breast cancer. This review provides insights into the mechanism of exosome-derived ncRNAs in breast cancer drug resistance, thereby suggesting new strategies for the treatment of BC.

Potential therapeutic targets of the JAK2/STAT3 signaling pathway in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its propensity for metastasis and poor prognosis. TNBC evades the body's immune system recognition and attack through various mechanisms, including the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. This pathway, characterized by heightened activity in numerous solid tumors, exhibits pronounced activation in specific TNBC subtypes. Consequently, targeting the JAK2/STAT3 signaling pathway emerges as a promising and precise therapeutic strategy for TNBC. The signal transduction cascade of the JAK2/STAT3 pathway predominantly involves receptor tyrosine kinases, the tyrosine kinase JAK2, and the transcription factor STAT3. Ongoing preclinical studies and clinical research are actively investigating this pathway as a potential therapeutic target for TNBC treatment. This article comprehensively reviews preclinical and clinical investigations into TNBC treatment by targeting the JAK2/STAT3 signaling pathway using small molecule compounds. The review explores the role of the JAK2/STAT3 pathway in TNBC therapeutics, evaluating the benefits and limitations of active inhibitors and proteolysis-targeting chimeras in TNBC treatment. The aim is to facilitate the development of novel small-molecule compounds that target TNBC effectively. Ultimately, this work seeks to contribute to enhancing therapeutic efficacy for patients with TNBC.

Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer.

The deficiency in available targeted agents and frequency of chemoresistance are primary challenges in clinical management of triple-negative breast cancer (TNBC). The aberrant expression of USP21 and JAK2 represents a characterized mechanism of TNBC progression and resistance to paclitaxel (PTX). Despite its clear that high expression of USP21-mediated de-ubiquitination leads to increased levels of JAK2 protein, we lack regulator molecules to dissect the mechanisms that the interaction between USP21 and JAK2 contributes to the phenotype and resistance of TNBC. Here, we report a USP21/JAK2/STAT3 axis-targeting regulator 13c featuring a N-anthraniloyl tryptamine scaffold that showed excellent anti-TNBC potency and promising safety profile. Importantly, the therapeutic potential of using 13c in combination with PTX in PTX-resistant TNBC was demonstrated. This study showcases N-anthraniloyl tryptamine derivatives as a novel anti-TNBC chemotype with a pharmacological mode of action targeting the USP21/JAK2/STAT3 axis and provides a potential therapeutic target for the treatment of TNBC.

Autophagy-related ncRNAs: Regulatory Roles and Potential Therapeutic Effects in Digestive System Neoplasms.

Among all cancers in the world, the incidence rate of digestive system neoplasms accounts for about 25%, while the mortality rate accounts for about 35%. Difficulty in detecting early digestive system cancers and its poor prognosis are the two main reasons for the high mortality rate. Understanding of the basic cellular processes is of significance and autophagy is one of these processes. Considering the importance of autophagy in pathological state functions, the mechanism of autophagy was initially carried out. In this paper, we will review the molecular mechanisms and biological functions of autophagy-associated ncRNAs in different types of digestive system cancers. Autophagy is a process that supports nutrient cycling and metabolic adaptation accomplished through multi-step lysosomal degradation. It has been suggested that autophagy has a dual role in cancer, which limits tumorigenesis in some stages but promotes tumor progression in others. NcRNAs are also shown to modulate cellular autophagy and thus affect the development of digestive system neoplasms. More and more evidence suggests that the regulation of autophagy by ncRNAs plays a complex role in cancer initiation, progression, metastasis, recurrence, and treatment resistance, which might make ncRNAs therapeutic targets for digestive system neoplasms. While miRNAs participate mainly in post-transcriptional regulation, lncRNAs, and circRNAs usually serve as molecular sponges that have more diverse regulatory functions.

LncRNA TUG1 and its Molecular Mechanisms in Human Cancer.

As lncRNAs have increasingly been investigated, they are no longer simply defined as RNAs with no transcription capability. Studies have identified significant associations between the abnormal expression of lncRNAs and human diseases, particularly the mechanisms by which lncRNAs play a part in cancers, which are of considerable attention to researchers. As a result of the complex spatial structure, the mechanisms of interaction of lncRNAs in cancer cells are also complicated and diversified. Among a series of lncRNAs, TUG1, which is now considered to be a very high-value lncRNA, has recently been identified to express abnormally in some malignancies, leading to different alterations in cancer cells proliferation, migration, invasion, apoptosis, and drug resistance, and hence promoting or inhibiting cancer progression. Current studies have implicitly indicated that TUG1 can be used as a therapeutic target for human cancers. However, the biological functions of TUG1 have been studied for a short period of time, and the complete molecular mechanism still needs to be clarified. Accordingly, this review focuses on the principal molecular mechanisms of TUG1 in human cancers and the specific mechanisms of action in different cancer development processes based on existing studies.

The Cross-Talk of Non-coding RNAs and Inflammation in Human Cancer.

Despite advanced clinical treatment, the mortality rate of cancer patients is high. Recent studies have linked the development of cancer to inflammation. Many cancers are exacerbated by the emergence of inflammatory responses, and non-coding RNAs play an important role in inflammation. Non-coding RNAs include microRNAs, circular RNAs, long-chain noncoding RNAs, etc. The non-coding RNA regulatory network composed of microRNAs, circular RNAs and long-chain non-coding RNAs is involved in the regulatory process of multiple gene expression. They can act on various signaling pathways, such as wnt/ß-catenin, nuclear factorkappa B, phosphatidylinositol 3 kinase/ AKT, mitogen-activated protein kinase, and so on. These signaling pathways can control the occurrence of inflammatory response to some extent, such as regulating the expression of inflammatory cytokines (such as interleukin-6, interferongamma, tumor necrosis factor-α, and so on), making them upregulated or down-regulated. Therefore, it is important to study the role of non-coding RNAs in inflammation to contribute to the future of cancer.

Small-molecule modulators of tumor immune microenvironment.

In recent years, tumor immunotherapy, aimed at increasing the activity of immune cells and reducing immunosuppressive effects, has attracted wide attention. Among them, immune checkpoint blocking (ICB) is the most commonly explored therapeutic approach. All approved immune checkpoint inhibitors (ICIs) are clinically effective monoclonal antibodies (mAbs). Compared with biological agents, small-molecule drugs have many unique advantages in tumor immunotherapy. Therefore, they also play an important role. Immunosuppressive signals such as PD-L1, IDO1, and TGF-ß, etc. overexpressed in tumor cells form the tumor immunosuppressive microenvironment. In addition, the efficacy of multi-pathway combined immunotherapy has also been reported and verified. Here, we mainly reviewed the mechanism of tumor immunotherapy, analyzed the research status of small-molecule modulators, and discussed drug candidates' structure-activity relationship (SAR). It provides more opportunities for further research to design more immune small-molecule modulators with novel structures.

The Emerging Roles of Circpvt1 in Cancer Progression.

CircRNA is stable due to its ring structure and is abundant in humans, which not only exists in various tissues and biofluids steadily but also plays a significant role in the physiology and pathology of human beings. CircPVT1, an endogenous circRNA, has recently been identified from the PVT1 gene located in the cancer risk region 8q24. CircPVT1 is reported to be highly expressed in many different tumors, where it affects tumor cell proliferation, apoptosis, invasion, and migration. We summarize the biosynthesis and biological functions of circPVT1 and analyze the relationship between circPVT1 and tumors as well as its significance to tumors. Further, it's noteworthy for the diagnosis, treatment, and prognosis of cancer patients. Therefore, circPVT1 is likely to become an innovative tumor marker.

Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

pH regulators and their inhibitors in tumor microenvironment.

As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets.

The Impact of miR-122 on Cancer.

MiRNAs are confirmed to be a kind of short and eminently conserved noncoding RNAs, which regulate gene expression at the post-transcriptional level via binding to the 3'- untranslated region (3'-UTR) of targeting multiple target messenger RNAs. Recently, growing evidence stresses the point that they play a crucial role in a variety of pathological processes, including human cancers. Dysregulated miRNAs act as oncogenes or tumor suppressor genes in many cancer types. Among them, we noticed that miR-122 has been widely reported to significantly influence carcinogenicity in a variety of tumors by regulating target genes and signaling pathways. Here, we focused on the expression of miR-122 in regulatory mechanisms and tumor biological processes. We also discussed the effects of miR-122 dysregulation in various types of human malignancies and the potential to develop new molecular miR-122-targeted therapies. The present review suggests that miR-122 may be a potentially useful cancer diagnosis and treatment biomarker. More clinical diagnoses need to be further launched in the future. A promising direction to improve the outcomes for cancer patients will likely combine miR-122 with other traditional tumor biomarkers.

Efficacy of Chemoimmunotherapy versus Chemotherapy for Gastric Cancer: A Meta-Analysis of Survival Outcomes.

BACKGROUND: Gastric cancer has been traditionally treated with chemotherapy as the primary mode of treatment. However, recent studies have shown that chemoimmunotherapy is also effective and, in some cases, better than chemotherapy treatment. Current study aimed to find the efficacy of chemoimmunotherapy versus chemotherapy in the treatment of gastric cancer. METHODS: Using electronic databases, including PubMed, Embase, and EBSCO, a thorough literature search was carried out for the years 2006 to 2023. The search strategy was designed to identify relevant studies based on chemoimmunotherapy and chemotherapy intervention, and the search was conducted using appropriate keywords and MeSH terms. The retrieved studies were screened for relevance based on their titles, abstracts, and full texts. The studies' inclusion criteria were predefined, and the selected studies were then subjected to a quality assessment using GradePro GDT. The data from selected studies were extracted and analyzed using Revman version 5.4. RESULTS: The study found that chemoimmunotherapy treatment resulted in a significant improvement in overall survival (OS) with a risk ratio (RR) of 1.54 and a 95% Confidence Interval (CI) of 1.25 to 1.89. The overall effect was also found to be significant, with a p-value of less than 0.001. Furthermore, we also observed an improvement in the 1-year, 3-year, and 5-year survival rates with risk ratio (RR) of 1.09 (95% CI: 1.01, 1.17), 1.43 (95% CI: 1.28, 1.60), and 1.59 (95% CI: 1.10, 2.30), respectively. In addition, it's also found that chemoimmunotherapy treatment also resulted in an improvement in DFS with an RR of 1.94 and a 95% CI of 1.44 to 2.59. Overall, these results suggest that chemoimmunotherapy treatment can be an effective approach in comparison to chemotherapy for improving overall survival and disease-free survival in the studied population. CONCLUSION: This study comparing chemoimmunotherapy versus chemotherapy for gastric cancer showed that both treatments were effective, but chemoimmunotherapy had more significant efficacy. To support these results, additional studies with a large sample size and a longer follow-up time are required.

Emerging roles of ncRNAs regulating ABCC1 on chemotherapy resistance of cancer - a review.

In the process of chemotherapy, drug resistance of cancer cells is a common and difficult problem of chemotherapy failure, and it is also the main cause of cancer recurrence and metastasis. Non-coding RNAs (ncRNAs) refer to the RNA that does not encode proteins, including microRNA (miRNA), long non-coding RNA (lncRNA) and circularRNA (circRNA), etc. NcRNAs are involved in a series of important life processes and further regulate the expression of ABCC1 by directly or indirectly up-regulating or down-regulating the expression of targeted mRNAs, making cancer cells more susceptible to drug resistance. A growing number of studies have shown that ncRNAs have effects on cancer cell proliferation, invasion, metastasis, and drug sensitivity, by regulating the expression of ABCC1. In this review, we will discuss the emerging roles of ncRNAs regulating ABCC1 in chemotherapy resistance and mechanisms to reverse drug resistance as well as provide potential targets for future cancer treatment.

Emerging role of competing endogenous RNA in lung cancer drug resistance.

Lung cancer remains one of the most common malignant cancers worldwide, and its survival rate is extremely low. Chemotherapy, the mainstay of lung cancer treatment, is not as effective as it could be due to the development of cellular resistance. The molecular mechanisms of drug resistance in lung cancer remain to be elucidated. Accumulating evidence suggests that ceRNAs are involved in various carcinogenesis and development. CeRNA is a transcript that regulates each other through competition with miRNA. However, the relationship between ceRNAs and chemoresistance in lung cancer remains unclear. In this narrative review, we provided a summary of treatment approaches that focus on ceRNA networks to overcome drug resistance.

Current Perspectives of Immunotherapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma is the sixth most common tumor and the third leading cause of cancer death worldwide. It ranks fourth in the spectrum of malignant tumor incidence and second in the order of death from major malignant tumors in China. Hepatocellular carcinoma is a complex ecosystem containing non-tumor cells (mainly immune-related cells), and its immunotherapy can stimulate the recognition of specific tumor antigens, inhibit the proliferation of cancer cells, and produce over-memory lymphocytes, which can prevent recurrence. So, immunotherapy of hepatocellular carcinoma is increasingly becoming a research hotspot in liver cancer treatment. With the intensive research in recent years, great progress has been made in immunotherapy for hepatocellular carcinoma, including immune checkpoint inhibitors, pericyte therapy, vaccination, and antiviral therapy. In addition, the study found that the therapeutic effect of combination therapy was enhanced compared to monotherapy. This review summarizes the most prominent immunotherapies currently available for the clinical treatment of patients with HCC and the main opportunities and challenges facing HCC research.

[Construction and evaluation of a nomogram prediction model for periprosthetic fractures after total hip arthroplasty].

OBJECTIVE: To construct and evaluate nomogram prediction model for periprosthetic fractures in patients undergoing total hip arthroplasty (THA). METHODS: A total of 538 patients who underwent THA from April 2013 to February 2019 were selected as the research subjects, including 318 males and 220 females, aged 40 to 60 years old with an average age of (50.79±6.37) years old. All patients with THA were divided into non-fracture group (506 patients) and fracture group (32 pathents) according to the 3-year follow-up results. Univariate and multivariate Logistic regression analyses were performed to analyze the influencing factors of postoperative periprosthetic fractures in patients with THA. A nomogram prediction model for periprosthetic fractures in patients undergoing THA was constructed, and the validity and discrimination of the prediction model were evaluated. RESULTS: The proportion of patients with osteoporosis, trauma history, and hip revision in the fracture group were higher than those in the non-fracture group(P<0.05), and the proportion of bone cement prosthesis was lower than that in the non-fracture group(P<0.05). The osteoporosis status[OR=4.177, 95%CI(1.815, 9.617), P<0.05], trauma history[OR=7.481, 95%CI(3.104, 18.031), P<0.05], and hip revision[OR=11.371, 95%CI(3.220, 40.153, P<0.05] were independent risk factors for postoperative periprosthetic fractures in patients undergoing THA, cemented prosthesis [OR=0.067, 95%CI(0.019, 0.236), P<0.05] was an independent protective factor for postoperative periprosthetic fractures in patients undergoing THA(P<0.05). Hosmer-Lemeshow goodness of fit test showed that χ2=7.864, P=0.325;the area under the curve (AUC) for periprosthetic fractures in patients undergoing THA was 0.892 with a sensitivity of 87.5% and a specificity of 77.7% by receiver operating characteristic(ROC) curve. CONCLUSION: The nomogram prediction model for periprosthetic fractures after THA constructed in this study has good discrimination, which is beneficial to clinical prediction of periprosthetic fractures in patients undergoing THA, and facilitates individualized fracture prevention.

The Progress of Small Molecule Targeting BCR-ABL in the Treatment of Chronic Myeloid Leukemia.

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease. According to the American Cancer Society's 2021 cancer data report, new cases of CML account for about 15% of all leukemias. CML is generally divided into three stages: chronic phase, accelerated phase, and blast phase. Nearly 90% of patients are diagnosed as a chronic phase. Allogeneic stem cell transplantation and chemotherapeutic drugs, such as interferon IFN-α were used as the earliest treatments for CML. However, they could generate obvious side effects, and scientists had to seek new treatments for CML. A new era of targeted therapy for CML began with the introduction of imatinib, the first-generation BCR-ABL kinase inhibitor. However, the ensuing drug resistance and mutant strains led by T315I limited the further use of imatinib. With the continuous advancement of research, tyrosine kinase inhibitors (TKI) and BCR-ABL protein degraders with novel structures and therapeutic mechanisms have been discovered. From biological macromolecules to classical target protein inhibitors, a growing number of compounds are being developed to treat chronic myelogenous leukemia. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in CML therapy, including TKIs and BCR-ABL protein degrader. The examples provided herein describe the pharmacology activity of small-molecule drugs. These drugs will provide new enlightenment for future treatment directions.

Research and development of N,N'-diarylureas as anti-tumor agents.

Tumor neovascularization provides abundant nutrients for the occurrence and development of tumors, and is also an important factor in tumor invasion and metastasis, which has attracted extensive attention in anti-tumor therapy. Sorafenib is a clinically approved multi-targeted anti-tumor drug that targets vascular endothelial growth factor receptor (VEGFR) and inhibits the formation of tumor angiogenesis, thereby achieving the purpose of suppressing tumor growth. Since the approval of sorafenib, N,N'-diarylureas have received extensive attention as the key pharmacophore in its chemical structure. And a series of N,N'-diarylureas were designed and synthesized to screen a new generation of anti-tumor drug candidates through chemical modification and structural optimization. Moreover, the rational design of targeted drugs is beneficial to reduce toxic side effects and drug resistance and improve the curative effect. Here, this article reviews the research progress in the design, classification, structure-activity relationship (SAR) and biological activity of N,N'-diarylureas, in order to provide some prospective routes for the development of clinically effective anti-tumor drugs.

Emerging roles of noncoding RNAs in human cancers.

Studies have found that RNA encoding proteins only account for a small part of the total number, most RNA is non-coding RNA, and non-coding RNA may affect the occurrence and development of human cancers by affecting gene expression, therefore play an important role in human pathology. At present, ncRNAs studied include miRNA, circRNA, lncRNA, piRNA, and snoRNA, etc. After decades of research, the basic role of these ncRNAs in many cancers has been clear. As far as we know, the role of miRNAs in cancer is one of the hottest research directions, however, it is also found that the imbalance of ncRNAs will affect the occurrence of gastric cancer, breast cancer, lung cancer, meanwhile, it may also affect the prognosis of these cancers. Therefore, the study of ncRNAs in cancers may help to find new cancer diagnostic and treatment methods. Here, we reviewed the biosynthesis and characteristics of miRNA, cricRNA, and lncRNA etc., their roles in human cancers, as well as the mechanism through which these ncRNAs affect human cancers.

Synthesis and anti-hepatocellular carcinoma evaluation of salicylic acid-modified indole trimethoxy flavonoid derivatives.

Simultaneous inhibition of tumor vasculature and the glycolysis pathway may be a targeted anti-tumor strategy to inhibit tumor nutrient supply. Flavonoids are natural products with strong biological activity, which inhibit hypoxia induction factor 1α (HIF-1α) regulating glycolysis and tumor angiogenesis, while salicylic acid can reduce the glycolysis level of tumor cells by inhibiting related rate-limiting enzymes. A series of salicylic acid-modified indole trimethoxy-flavone derivatives were designed and synthesized by introducing benzotrimethoxy-structure commonly used in blood vessel blockers, and their anti-tumor activities were evaluated. Among them, compound 8f exhibited significant anti-proliferative activity against two hepatoma cells, HepG-2 and SMMC-7721, with IC50 values of 4.63 ± 1.13 µM and 3.11 ± 0.35 µM, respectively. Colony formation experiments also further verified its excellent in vitro anti-tumor activity. In addition, compound 8f showed the ability to induce apoptosis in SMMC-7721 cells in a concentration-dependent manner. After treatment with compound 8f, the expressions of the rate-limiting enzymes PKM2, PFKM, HK2 and tumor angiogenesis-related vascular endothelial growth factor of the glycolytic pathway were all down-regulated, and the lactate level in the hepatoma cell SMMC-7721 was significantly reduced. The morphology of the nucleus and tubulin was also observed to disperse gradually with the increase of compound 8f concentration. And compound 8f showed strong binding ability to tubulin. Our results suggest that the strategy of synthesizing the salicylic acid-modified indole flavone derivative 8f is a way to obtain active anti-tumor candidate compounds that may be further developed as targeted agents to inhibit tumor vasculature and glycolytic pathways.