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Background: Dual HER2 targeted therapy with trastuzumab (H) and pertuzumab (P) has been approved as neoadjuvant therapy for patients with HER2-positive breast cancer in China in 2019 based on the results from NeoSphere and PEONY study. However, the real-world efficacy and safety data are currently lack of evidence in China. Therefore, this multi-center real-world study aims to retrospectively analyze the efficacy and safety of neoadjuvant trastuzumab and pertuzumab combined with different chemotherapy regimens of HER2-positive early breast cancer. Methods: Patients received trastuzumab and pertuzumab in combination with different chemotherapy regimens, including taxanes (T), cyclophosphamide (C), anthracyclines (A) were collected retrospectively from 12 centers. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate. Results: A total of 357 patients were enrolled, among which 204 (57.5%) recieved TCbHP, 92 (25.9%) recieved EC-THP, and 51 (14.4%) received THP as chemotherapy regimens. The median age was 48 years old (range, 22-76), 142 (39.8%) of patients were classified as hormone receptor (HR)-positive, and 215 (60.2%) were HR-negative. The overall tpCR rate was 58.5% (95%CI, 53.2%-63.7%). tpCR rate for HR-negative patients was significantly higher than HR-positive patients (65.6% vs. 47.9%, p=0.001) and there was not any statistical difference according to chemotherapy regimens (56.9% for TCbHP, 56.5% for EC-THP, and 66.7% for THP, p=0.445). The most common adverse events included anemia (40.1%), white blood cell count decreased (34.3%), ejection fraction decreased (19.5%), Alanine aminotransferase increased (18.9%), platelet count decreased (12.8%) and neutrophil count decreased (12.0%). There was not any toxicity leading to death. Conclusions: Multi-center real-world data show satisfactory tpCR rate and tolerable adverse events of trastuzumab and pertuzumab in combination with different chemotherapy regimens in China. Citation Format: Xiaowei Qi, Hong Hu, chen wenlin, xu yan, liu shu, fang yanman, Taolang Li, ming jia, zhou sihai, chai fan, liang yueyang, fan yuanming, Yi Zhang, Peng Tang, jiang jun, nie jianyun, Li Chen, Shushu Wang. The efficacy and safety of trastuzumab and pertuzumab in combination with different chemotherapy regimens for neoadjuvant treatment of HER2-posotive breast cancer: a multi-center real-world study in China [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-18.

Goals: Ion transporters play an important regulatory role in the progression and development of breast cancer (BC). Slc26a9 is a member of the Slc26a anion transporter family, which is mainly involved in regulating the secretion of chloride ions and bicarbonate, but the role of Slc26a9 in HER2-positive BC is still unclear. Methods: Tissue microarray and BC cell line were used to detect the expression level of Slc26a9 and its clinical relevance. By changing the expression level of Slc26a9 gene in BC cells, the effect of Slc26a9 gene on the biological behavior of BC cells and its related molecular mechanism were discussed. Results: We found that the expression of Slc26a9 was significantly upregulated in BC compared with adjacent tissues, and the upregulated Slc26a9 was associated with TNM staging and poor prognosis in BC patients. In addition, the expression of Slc26a9 was significantly upregulated in HER2-positive BC compared with HER2-negative BC, and similar results were obtained in BC cell lines, with Slc26a9 was the highest expression in HER2-enriched SKBR3 cells. Functionally, the proliferation, migration, invasion and anti-apoptotic abilities of SKBR3 cells were significantly inhibited after silencing Slc26a9, and tumorigenesis and metastasis were significantly inhibited in vivo. On the contrary, overexpression of Slc26a9 resulted in the opposite result. Mechanistically, overexpression of Slc26a9 activated the PI3K/AKT/mTOR signaling pathway, the key signaling pathway implicated in HER2-positive breast carcinogenesis, and promoted the expression of downstream proliferation related genes CCND1 (Cyclin D1) and c-Myc, and downregulated the expression of apoptosis related genes Caspase9, apoptosis-inducing factor (AIF) and endonuclease G (Endo G), indicating the simultaneous inhibition of caspase dependent and independent apoptosis pathway. At the same time, accompanied by changes in markers of epithelial-mesenchymal transition (EMT), including downregulation of E-cadherin and ZO-1, and upregulation of N-cadherin and Fibronectin, and SKBR3 cells changed from epithelioid morphology to mesenchymal morphology. In addition, immunofluorescence and protein nucleoplasm separation experiments showed that Slc26a9 upregulated the expression of HER2 and co-localized with HER2 in the nucleus. Co-immunoprecipitation experiments proved that Slc26a9 interacted with HER2. Furthermore, trastuzumab downregulated the expression of Slc26a9 by targeting HER2 in SKBR3 cells. Moreover, when Slc26a9 was overexpressed, the inhibitory effect of trastuzumab on HER2 was partially reversed, and we also verified the PI3K/AKT/mTOR signaling pathway. Not only that, we found that Slc26a9 was significantly upregulated in drug-resistant cell lines relative to parental cells by constructing SKBR3 drug-resistant cell lines, indicating that Slc26a9 expression was significantly correlated with chemotherapy resistance in HER2-positive BC. Conclusion(s): Slc26a9 may interact with HER2 in the form of molecular chaperones to activate PI3K/AKT/mTOR signaling pathway to promote the progression and development of HER2-positive BC and be associated with chemotherapy resistance, but the precise molecular mechanism needs further exploration. Conflict of Interest: No significant relationships. Citation Format: Zhengxing Zhou, Zhiyuan Ma, Xuemei Liu, Chengmin Zhang, Hu Wang, Renmin Mu, Xiaoming Cheng, Biguang Tuo, Taolang Li. Slc26a9 cooperates with HER2 to regulate the progression and development of HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-19.

The incidence of gastrointestinal (GI) mucosal diseases, including various types of gastritis, ulcers, inflammatory bowel disease and GI cancer, is increasing. Therefore, it is necessary to identify new therapeutic targets. Ion channels/transporters are located on cell membranes, and tight junctions (TJs) affect acid–base balance, the mucus layer, permeability, the microbiota and mucosal blood flow, which are essential for maintaining GI mucosal integrity. As ion channel/transporter dysfunction results in various GI mucosal diseases, this review focuses on understanding the contribution of ion channels/transporters to protecting the GI mucosal barrier and the relationship between GI mucosal disease and ion channels/transporters, including Cl−/HCO3− exchangers, Cl− channels, aquaporins, Na+/H+ exchangers, and K+ channels. Here, we provide novel prospects for the treatment of GI mucosal diseases.

Background Nesidioblastosis and insulinomas are caused by dysfunctional β cells, which in turn can cause endogenous hyperinsulinemia. In adults, the clinical and histomorphological features of nesidioblastosis and insulinoma may be remarkably similar, implying that it can be difficult to differentiate the two entities with preoperative biochemical and diagnostic imaging. Case presentation We report a 48-year-old man diagnosed with adult focal nesidioblastosis. We used contrast-enhanced magnetic resonance imaging (ceMRI), [68Ga]-DOTATATE positron-emission tomography/computed tomography (PET/CT), endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) and other tests before surgery, all of which highly suggested insulinoma. However, the final pathological diagnosis was focal neuroblastoma. Conclusion Adult focal nesidioblastosis is very rare. In this case, we focused on differentiating focal nesidioblastosis from insulinoma. We reviewed relevant literature reports and found that it is sometimes difficult to differentiate the two diseases with the results of preoperative examinations. For pancreatic space-occupying lesions that can clinically present as either of these two diseases, the focus should be on distinguishing between the presence and absence of metastases as well as precise pancreatic localization.

MicroRNAs (miRNA) have been shown to be associated with tumor diagnosis, prognosis, and therapeutic response. MiR-328-3p plays a significant role in breast cancer growth; however, its actual function and how it modulates specific biological functions is poorly understood. Here, miR-328-3p was significantly downregulated in breast cancer, especially in patients with metastasis. Mitochondrial carnitine palmitoyl transferase 1a (CPT1A) is a downstream target gene in the miR-328-3p-regulated pathway. Furthermore, the miR-328-3p/CPT1A/fatty acid β-oxidation/stemness axis was shown responsible for breast cancer metastasis. Collectively, this study revealed that miR-328-3p is a potential therapeutic target for the treatment of breast cancer patients with metastasis, and also a model for the miRNA-fatty acid β-oxidation-stemness axis, which may assist inunderstanding the cancer stem cell signaling functions of miRNA.

Background: Slc26a9 (Solute carrier family 26 member 9) is a member of Slc26a family of multifunctional anion transporters, which functions as Cl- channel (Liu et al., Front Physiol 2018). Our previous study showed that SLC26A9 deficiency results in the development and progression of gastric cancer, which demonstrated that the key role of SLC26A9 in the tumorigenesis first time (Liu et al., Gastroenterology 2018). However, what’s the role of SLC26A9 in the breast cancer (BC) onset is not clear. We therefore wondered whether Slc26a9 gene is involved in promoting breast carcinogenesis and its mechanisms. Methods: The tissue microarrays and IHC assay were used to detect the expression and clinic relevance of SLC26A9 in the human BC. Different BC cell lines were used to investigate the expression and function of SLC26A9 in the BC. SLC26A9 gene transfect and knockout experiment were performed to detect the regulator role of SLC26A9 in BC cell behaviors. Results: Compared with adjacent normal tissues, SLC26A9 expression was significantly increased in the BC tissue, SLC26A9 expression level in BC correlated with the differentiated state of BC and patient’s clinical outcome, indicating that SLC26A9 may be involved in BC pathogenesis and progression in humans and it might be a novel poor prognosis marker for BC. Moreover, HER2 positive BC tissues exhibited high SLC26A9 expression than HER2 negative BC tissues. Compared with normal mammary cell line, SLC26A9 was significantly upregulated in the all BC cell lines, with highest expression in HER2 enriched cell line SKBR3. Deletion of SLC26A9 in SKBR3 resulted in inhibition of BC cell proliferation, migration and invasion, but promotion of cell apoptosis, which were investigated by different cell function assays, including cell counting Kit-8, cell proliferation curve, Annexin VFITC/PI double staining, Wound-healing and transwell assays respectively. Moreover, SLC26A9 deficiency in SKBR3 caused alteration of epithelial mesenchymal transition (EMT) markers, including downregulation of N-cadherin, Snail1, Fibronectin and Vimentin, but increasement of E-cadherin and ZO-1, accompany with disrupting TGFβ signaling pathways, including downregulation of TGF-β1, p-Smad2 and p-Smad3. However, overexpression of SLC26A9 in SKBR3 resulted in inhibition of cell proliferation, migration and invasion, but promotion of cell apoptosis. Accompanying with activation of TGFβ pathway mediate EMT. Conclusions: Upregulation of SLC26A9 resulted in the development and progression of HER2 positive BC via activation of TGFβ signaling pathways. SLC26A9 might be a novel prognosis marker and therapeutic target for BC. Citation Format: Zhiyuan Ma, Xuemei Liu, Chengli Lu, Jiaxing Zhu, Xiaoming Cheng, Biguang Tuo, Taolang Li. Upregulation of SLC26A9 resulted in the development and progression of HER2 positive breast cancer via activating TGFβ signaling pathway [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-27.

Thyroid cancer is the most common type of endocrine tumor and has shown an increasing annual incidence, especially among women. Patients with thyroid cancer have a good prognosis, with a high five-year survival rate; however, the recurrence rate and disease status of thyroid cancer remain a burden for patients, which compels us to further elucidate the pathogenesis of this disease. Recently, ion transporters have gradually become a hot topic in the field of thyroid gland biology and cancer research. Additionally, alterations in the metabolic state of tumor cells and protein molecules have gradually become the focus of scientific research. This review focuses on the progress in understanding the physiological and pathophysiological roles of ion transporter-mediated metabolism in both the thyroid gland and thyroid cancer. We also hope to shed light on new targets for the treatment and prognosis of thyroid cancer.

Background Solute carrier family 26 member (SLC26A9) is a Cl− uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of slc26a9−/− mice and in selective parietal cell-deleted slc26a9fl/fl/Atp4b-Cre mice and correlate SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients. Methods The expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis. SLC26A9 expression and cellular/clinical phenotypes were studied in primary human GC tissues and GC cell lines. Results We found that both complete and parietal cell-selective Slc26a9 deletion in mice caused spontaneous development of gastric premalignant and malignant lesions. Dysregulated differentiation of gastric stem cells in an inflammatory environment, activated Wnt signaling, cellular hyperproliferation, apoptosis inhibition and metaplasia were observed. Analysis of human gastric precancerous and cancerous tissues revealed that SLC26A9 expression progressively decreased from atrophic gastritis to GC, and that downregulation of SLC26A9 was correlated with patient survival. Exogenous expression of SLC26A9 in GC cells induced upregulation of the Cl−/HCO3− exchanger AE2, G2/M cell cycle arrest and apoptosis and suppressed their proliferation, migration and invasion. Conclusions Our data indicate that SLC26A9 deletion in parietal cells is sufficient to trigger gastric metaplasia and the development of neoplastic lesions. In addition, we found that SLC26A9 expression decreases during human gastric carcinogenesis, and that exogenous SLC26A9 expression in GC cells reduces their malignant behavior. Graphical abstract

As the most common malignant tumor, the incidence of papillary thyroid carcinoma (PTC) has been significantly increased over the past few years. Approximately 30%-90% of patients with PTC present with cervical lymph node metastasis (LNM) at the time of initial diagnosis or follow-up, which has a serious impact on survival and prognosis. Six PTC N0 samples and six PTC N1b samples were collected. Proteins from the samples were analyzed by label-free quantitative proteomics. The bioinformatics of differentially expressed proteins (DEPs) was annotated with bioinformatic tools. The protein expression levels of the hub genes were verified using the HPA databases. Finally, we used the GEPIA database to perform survival analysis for the hub genes. A total of 1407 proteins were quantified under highly stringent criteria with fold change ≥ 2.0 and P

Portal hypertensive gastropathy (PHG) is a complication of cirrhotic or noncirrhotic portal hypertension. PHG is very important in the clinic because it can cause acute or even massive blood loss, and its treatment efficacy and prognosis are poor. Currently, the incidence of PHG in patients with cirrhosis is 20-80%, but its pathogenesis is complicated and poorly understood. Studies have shown that portal hypertension can cause changes in gastric mucosal microcirculation hemodynamics, leading to changes in gastric mucosal histology and function and thereby weakening the mucosal defense barrier. However, no specific drug treatment plans are currently available. This article reviews the current literature to further our understanding of the mechanism underlying PHG and the relationship between PHG and the posterior mucosal defense barrier and to explore new therapeutic targets.

BackgroundThe mapping method represents a crucial factor affecting the rate of sentinel lymph node detection in breast cancer. We carried out this meta-analysis to assess the clinical utility of carbon nanoparticle suspensions (CNSs) in guiding sentinel lymph node biopsy (SLNB) for breast cancer patients.MethodsElectronic databases, which comprised the China National Knowledge Infrastructure, the Wanfang electronic database, the Cochrane Library, EMBASE, and PubMed, were explored to identify relevant studies from database inception to July 2021 that studied the detection rate of CNSs-guided SLNB. A meta-analysis was performed to generate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), a summary receiver operator characteristic curve (SROC), and a diagnostic odds ratio (DOR).ResultsA total of 33 publications that enrolled 2,171 patients were analyzed. The pooled sensitivity, specificity, PLR, and NLR were 0.93 (95% CI: 0.91–0.95, I2 = 0.0%), 0.99 (95% CI: 0.98–0.99, I2 = 56.5%), 42.85 (95% CI: 29.73–61.77, I2 = 47.0%), and 0.09 (95% CI: 0.07–0.11, I2 = 0.0%), respectively. The area under the curve (AUC) of the SROC curve was 0.98. There were no significant differences when analyzed based on the dose and site of CNS injection. There was significant publication bias among the included publications based on Deeks’ funnel plot [Slope (Bias) = −7.35, P = 0.00]. Nonetheless, the sensitivity analysis identified the results to be reliable and stable.ConclusionThis meta-analysis highlights the accuracy and feasibility of using CNSs for SLNB in patients with breast cancer. Clinically, the identification and predictive values of CNSs as an optimal tracer for SLNB remains undisputed.

AIM Slc26a9 is a member of the Slc26 multifunctional anion transporter family. Polymorphisms in Slc26a9 are associated with an increased incidence of meconium ileus and diabetes in cystic fibrosis patients. We investigated the expression of Slc26a9 in the murine pancreatic ducts, islets and parenchyma, and elucidated its role in pancreatic ductal electrolyte and fluid secretion and endocrine function. METHODS Pancreatic Slc26a9 and CFTR mRNA expression, fluid and bicarbonate secretion were assessed in slc26a9-/- mice and their age- and sex-matched wild-type (wt) littermates. Glucose and insulin tolerance tests were performed. RESULTS Compared with stomach, the mRNA expression of Slc26a9 was low in pancreatic parenchyma, 20-fold higher in microdissected pancreatic ducts than parenchyma, and very low in islets. CFTR mRNA was ~10 fold higher than Slc26a9 mRNA expression in each pancreatic cell type. Significantly reduced pancreatic fluid secretory rates and impaired glucose tolerance were observed in female slc26a9-/- mice, whereas alterations in male mice did not reach statistical significance. No significant difference was observed in peripheral insulin resistance in slc26a9-/- compared to sex- and aged-matched wt controls. In contrast, isolated slc26a9-/- islets in short term culture displayed no difference in insulin content, but a significantly reduced glucose-stimulated insulin secretion compared to age- and sex-matched wt islets, suggesting that the impaired glucose tolerance in the absence of Slc26a9 expression these is a pancreatic defect. CONCLUSIONS Deletion of Slc26a9 is associated with a reduction in pancreatic fluid secretion and impaired glucose tolerance in female mice. The results underline the importance of Slc26a9 in pancreatic physiology.

The Oncotype DX 21-gene test can be used to predict chemotherapy efficacy in patients with estrogen receptor (ER)-positive and HER2-negative breast cancer; however, the data on the 21-gene recurrence score (RS) for mucinous breast carcinoma (MBC) are limited. The present study aimed to evaluate the distribution pattern and clinical value of the 21-gene RS in patients with MBC. A total of 38 pure MBC (PMBC) and 11 mixed MBC (MMBC) cases were retrospectively analyzed, and a total of 29 ER-positive and HER2-negative MBCs underwent the Oncotype DX 21-gene test. There were no statistically significant differences between the PMBCs and MMBCs in age, tumor size and molecular subtype; however, patients with MMBC showed a significantly higher incidence rate of nodal metastases compared with that in patients with PMBC (72.7 vs. 16.2%, respectively). Following surgery, 87.8 and 59.2% of the enrolled patients received endocrine therapy and chemotherapy, respectively. With a median follow-up of 65.6 months, the 5-year disease-free survival and overall survival rates were 97.0 and 100.0%, respectively. The 21-gene test revealed that the proportions of patients with MBC categorized into low (RS

The incidence of breast cancer (BC) has been increasing each year, and BC is now the most common malignant tumor in women. Among the numerous BC subtypes, HER2-positive BC can be treated with a variety of strategies based on targeting HER2. Although there has been great progress in the treatment of HER2-positive BC, recurrence, metastasis and drug resistance remain considerable challenges. The dysfunction of ion channels and transporters can affect the development and progression of HER2-positive BC, so these entities are expected to be new therapeutic targets. This review summarizes various ion channels and transporters associated with HER2-positive BC and suggests potential targets for the development of new and effective therapies.

Background Gastric cancer (GC) is one of the most common malignant cancers in the world and has only few treatment options and, concomitantly, a poor prognosis. It is generally accepted now that the tumor microenvironment, particularly that under hypoxia, plays an important role in cancer development. Hypoxia can regulate the energy metabolism and malignancy of tumor cells by inducing or altering various important factors, such as oxidative stress, reactive oxygen species (ROS), hypoxia-inducible factors (HIFs), autophagy and acidosis. In addition, altered expression and/or dysfunction of ion channels/transporters (ICTs) have been encountered in a variety of human tumors, including GC, and to play an important role in the processes of tumor cell proliferation, migration, invasion and apoptosis. Increasing evidence indicates that ICTs are at least partly involved in interactions between cancer cells and their hypoxic microenvironment. Here, we provide an overview of the different ICTs that regulate or are regulated by hypoxia in GC. Conclusions and perspectives Hypoxia is one of the major obstacles to cancer therapy. Regulating cellular responses and factors under hypoxia can inhibit GC. Similarly, altering the expression or activity of ICTs, such as the application of ion channel inhibitors, can slow down the growth and/or migration of GC cells. Since targeting the hypoxic microenvironment and/or ICTs may be a promising strategy for the treatment of GC, more attention should be paid to the interplay between ICTs and the development and progression of GC in such a microenvironment.

The incidence of thyroid cancer and breast cancer is increasing year by year, and the specific pathogenesis is unclear. Posttranslational modifications constitute an important regulatory mechanism that affects the function of almost all proteins, are essential for a diverse and well-functioning proteome and can integrate metabolism with physiological and pathological processes. In recent years, posttranslational modifications, which mainly include metabolic enzyme-mediated protein posttranslational modifications, such as methylation, phosphorylation, acetylation and succinylation, have become a research hotspot. Among these modifications, lysine succinylation is a newly discovered broad-spectrum, dynamic, non-enzymatic protein post-translational modification, and it plays an important regulatory role in a variety of tumors. Studies have shown that succinylation can affect the synthesis of thyroid hormones, and the regulation of this post-translational modification can inhibit the apoptosis and migration of thyroid cancer cell lines, and promote breast cancer cell proliferation, DNA damage repair and autophagy-related regulation. However, the specific regulatory mechanism of succinylation in thyroid cancer and breast cancer is currently unclear. Therefore, this article mainly reviews the research progress of succinylation modification in thyroid cancer and breast cancer. It is expected to provide new directions and targets for the prevention and treatment of thyroid cancer and breast cancer.

MicroRNAs (miRNA) have been shown to be associated with tumor diagnosis, prognosis, and therapeutic response. MiR-328-3p plays a significant role in breast cancer growth; however, its actual function and how it modulates specific biological functions is poorly understood. Here, miR-328-3p was significantly downregulated in breast cancer, especially in patients with metastasis. Mitochondrial carnitine palmitoyl transferase 1a (CPT1A) is a downstream target gene in the miR-328-3p-regulated pathway. Furthermore, the miR-328-3p/CPT1A/fatty acid β-oxidation/stemness axis was shown responsible for breast cancer metastasis. Collectively, this study revealed that miR-328-3p is a potential therapeutic target for the treatment of breast cancer patients with metastasis, and also a model for the miRNA-fatty acid β-oxidation-stemness axis, which may assist inunderstanding the cancer stem cell signaling functions of miRNA.

Previous study showed that Slc26a9 loss impairs parietal cell function and survival. We investigated whether Slc26a9 loss causes spontaneous gastric carcinogenesis in mice and plays a role in the development and progression in human gastric cancer (GC). Gastric histopathology and potential molecular mechanism were explored in Slc26a9 knockout mice and wild-type littermates as well as Slc26a9fl/fl/Atp4b-Cre and Slc26a9fl/fl mice from 8 days to 18 months by histological and immunohistochemical analyses, quantitative PCR, in situ hybridization, and RNA microarray analysis, respectively. We demonstrated that loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in mice, and clarified the sequence of events leading to malignant transformation, including Slc26a9 deficiency in parietal cells resulted in dysregulated differentiation of stem cells in an inflammatory environment, activated Wnt signaling pathway to induce gastric epithelia cell hyperproliferation and apoptosis inhibition, as well as spontaneous epithelial to mesenchymal transition-induced cancer stem cell phenotypes. Downregulation of SLC26A9 correlated with GC patient’s short survival.Graphical AbstractLoss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in transgenic mice.

Breast cancer is a common malignancy in women. Among breast cancer types, triple-negative breast cancer (TNBC) tends to affect younger women, is prone to axillary lymph node, lung, and bone metastases; and has a high recurrence rate. Due to a lack of classic biomarkers, the currently available treatments are surgery and chemotherapy; no targeted standard treatment options are available. Therefore, it is urgent to find a novel and effective therapeutic target. As alteration of ion channels and transporters in normal mammary cells may affect cell growth, resulting in the development and progression of TNBC, ion channels and transporters may be promising new therapeutic targets for TNBC. This review summarizes ion channels and transporters related to TNBC and may provide new tumor biomarkers and help in the development of novel targeted therapies.

The incidence of colorectal cancer has increased annually, and the pathogenesis of this disease requires further investigation. In normal colorectal tissues, ion channels and transporters maintain the water-electrolyte balance and acid/base homeostasis. However, dysfunction of these ion channels and transporters leads to the development and progression of colorectal cancer. Therefore, this review focuses on the progress in understanding the roles of ion channels and transporters in the colorectum and in colorectal cancer, including aquaporins (AQPs), Cl- channels, Cl- / HCO 3 - exchangers, Na+ / HCO 3 - transporters and Na+ /H+ exchangers. The goal of this review is to promote the identification of new targets for the treatment and prognosis of colorectal cancer.

Gastric mucosal injuries include focal and diffused injuries, which do and do not change the cell differentiation pattern. Parietal cells loss is related to the occurrence of gastric mucosal diffused injury, with two phenotypes of spasmolytic polypeptide-expressing metaplasia and neuroendocrine cell hyperplasia, which is the basis of gastric cancer and gastric neuroendocrine tumor respectively. Multiple ion channels and transporters are located and expressed in the parietal cells, which is not only regulate the gastric acid-base homeostasis, but also regulate the growth and development of parietal cells. Therefore, alteration and dysregulation of ion channels and transporters in the parietal cells impairs the morphology and physiological functions of stomach, resulted in gastric diffused mucosal damage. In this review, multiple ion channels and transporters in parietal cells, including K

Gastric cancer (GC) is a highly invasive and fatal malignant disease that accounts for 5.7% of new global cancer cases and is the third leading cause of cancer-related death. Acid/base homeostasis is critical for organisms because protein and enzyme function, cellular structure, and plasma membrane permeability change with pH. Various ion transporters are expressed in normal gastric mucosal epithelial cells and regulate gastric acid secretion, ion transport, and fluid absorption, thereby stabilizing the differentiation and homeostasis of gastric mucosal epithelial cells. Ion transporter dysfunction results in disordered ion transport, mucosa barrier dysfunction, and acid/base disturbances, causing gastric acid-related diseases such as chronic atrophic gastritis (CAG) and GC. This review summarizes the physiological functions of multiple ion transporters and channels in the stomach, including Cl−channels,Cl−/HCO3−exchangers, sodium/hydrogen exchangers (NHEs), and potassium (K+) channels, and their pathophysiological relevance in GC.

The incidence of breast cancer is increasing year by year, and the pathogenesis is still unclear. Studies have shown that the high metabolism of solid tumors leads to an increase in hypoxia, glycolysis, production of lactic acid and carbonic acid, and extracellular acidification; a harsh microenvironment; and ultimately to tumor cell death. Approximately 50% of locally advanced breast cancers exhibit hypoxia and/or local hypoxia, and acid-base regulatory proteins play an important role in regulating milk secretion and maintaining mammary gland physiological function. Therefore, ion transporters have gradually become a hot topic in mammary gland and breast cancer research. This review focuses on the research progress of ion transporters in mammary glands and breast cancer. We hope to provide new targets for the treatment and prognosis of breast cancer.

Acidic mammalian chitinase (CHIA) belongs to the 18-glycosidase family and is expressed in epithelial cells and certain immune cells (such as neutrophils and macrophages) in various organs. Under physiological conditions, as a hydrolase, CHIA can degrade chitin-containing pathogens, participate in Type 2 helper T (Th2)-mediated inflammation, and enhance innate and adaptive immunity to pathogen invasion. Under pathological conditions, such as rhinitis, ocular conjunctivitis, asthma, chronic atrophic gastritis, type 2 diabetes, and pulmonary interstitial fibrosis, CHIA expression is significantly changed. In addition, studies have shown that CHIA has an anti-apoptotic effect, promotes epithelial cell proliferation and maintains organ integrity, and these effects are not related to chitinase degradation. CHIA can also be used as a biomolecular marker in diseases such as chronic atrophic gastritis, dry eye, and acute kidney damage caused by sepsis. Analysis of the authoritative TCGA database shows that CHIA expression in gastric adenocarcinoma, liver cancer, renal clear cell carcinoma and other tumors is significantly downregulated compared with that in normal tissues, but the specific mechanism is unclear. This review is based on all surveys conducted to date and summarizes the expression patterns and functional diversity of CHIA in various organs. Understanding the physiological and pathophysiological relevance of CHIA in multiple organs opens new possibilities for disease treatment.

Purposes To improve the lymph node dissection as well as protect parathyroid gland and recurrent laryngeal nerve, the carbon nanoparticles and intraoperative neuromonitoring were applied in papillary thyroid microcarcinoma surgery. Methods Carbon nanoparticles and intraoperative neuromonitoring were used in the experimental group, whereas the control group were not. Routine pathological examination was performed. Results The lymph nodes dissected was significantly higher in the experimental group, but the metastatic lymph nodes were not. The number of mistakenly dissected parathyroid gland and postoperative hypoparathyroidism were 3 and 13 in the experimental group respectively, significantly less than 10 and 25 in the control group. The incidences of overall, transient and persistent recurrent laryngeal nerve palsy in the experimental group were 5.5%, 5.5% and 0% respectively, whereas in the control group were 8.6%, 6.9% and 1.7%. Conclusions Carbon nanoparticles can improve lymph node dissection in papillary thyroid microcarcinoma surgery, and the combination of carbon nanoparticles with intraoperative neuromonitoring can reduce surgical complications and improve patient quality of life.

Aim This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). Methods We assessed the ability of CAIX-knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pHi of exteriorized gastric mucosa in vivo using two-photon confocal laser scanning microscopy. Cytokines and claudin-18A2 expression was analysed by RT-PCR. Results CAIX-knockout gastric surface epithelial cells showed significantly faster pHi decline after luminal acid load compared to WT. Increased gastric mucosal IL-1β and iNOS, but decreased claudin-18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin-18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL-11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin-18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL-1β. However, the treatment reduced the parietal cell loss in CAIX-KO mice in the subsequent months. Conclusions We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO2 and H2O, contributing to tight junction protection and gastric epithelial pHi regulation. Lack of CAIX results in persistent acid backflux via claudin-18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.

Background:The anion transporter Slc26a9 is highly expressed in lung and stomach. We observed an excess perinatal mortality in Slc26a9-/- neonate mice. Aim and Methods: In search for the underlying cause, the dead pups were collected, genotyped, and examined histologically. Slc26a9 and CFTR mRNA expression was measured by qPCR in microdissected lung. Slc26a9-/-, CFTR-/-, and WT neonatal trachea were studied electrophysiologically in Ussing chambers. Results: Dead pups were Slc26a9-/- in >95%. Volume density measurements revealed a strong excess of tracheal and bronchial mucus in the Slc26a9-/- pups. Slc26a9 as well as CFTR mRNA expression was significantly higher in the distal than proximal airways, and significantly higher in neonatal than adult mice. The amiloride-insensitive, bumetanide-sensitive short circuit current (Isc) was higher in neonatal Slc26a9-/- than WT trachea, but lower in neonatal CFTR-/- than WT trachea. Surprisingly, forskolin (FSK) + IBMX elicited a significantly higher Isc response (...

Background: The exoenzyme carbonic anhydrase IX is strongly expressed in tumours. In normal tissues, CA IX is expressed during embryogenesis but downregulated postnatally, except in the stomach. Ai...