Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Recently, downregulation of microRNA-143 (miR-143) has been observed in CRC tissues. Here in this study, we found that miR-143 expression was downregulated both in CRC patients’ blood samples and tumor specimens. MiR-143 expression levels were strongly correlated with clinical stages and lymph node metastasis. Furthermore, insulin-like growth factor-I receptor (IGF-IR), a known oncogene, was a novel direct target of miR-143, whose expression levels were inversely correlated with miR-143 expression in human CRC specimens. Overexpression of miR-143 inhibited cell proliferation, migration, tumor growth and angiogenesis and increased chemosensitivity to oxaliplatin treatment in an IGF-IR-dependent manner. Taken together, these results revealed that miR-143 levels in human blood and tumor tissues are associated with CRC cancer occurrence, metastasis and drug resistance, and miR-143 levels may be used as a new diagnostic marker and therapeutic target for CRC in the future.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with high incidence and mortality, accounting for approximately 90% of liver cancer. The development of HCC is a complex process involving the abnormal activation or inactivation of multiple signaling pathways. Transforming growth factor-β (TGF-β)/Small mothers against decapentaplegic (SMAD) signaling pathway regulates the development of HCC. TGF-β activates intracellular SMADs protein through membrane receptors, resulting in a series of biological cascades. Accumulating studies have demonstrated that TGF-β/SMAD signaling plays multiple regulatory functions in HCC. However, there is still controversy about the role of TGF-β/SMAD in HCC. Because it involves different pathogenic factors, disease stages, and cell microenvironment, as well as upstream and downstream relationships with other signaling pathways. This review will summary the regulatory mechanism of the TGF-β/SMAD signaling pathway in HCC, involving the regulation of different pathogenic factors, different disease stages, different cell populations, microenvironments, and the interaction with microRNAs. In addition, we also introduced small molecule inhibitors, therapeutic vaccines, and traditional Chinese medicine extracts based on targeting the TGF-β/SMAD signaling pathway, which will provide future research direction for HCC therapy targeting the TGF-β/SMAD signaling pathway.

Heat stress is one of the main threats to dairy cow production; in order to resist heat stress, the animal exhibits a variety of physiological and hormonal responses driven by complex molecular mechanisms. Heat-stressed cows have high insulin activity, decreased non-esterified fatty acids, and increased glucose disposal. Glucose, as one of the important biochemical components of the energetic metabolism, is affected at multiple levels by the reciprocal changes in hormonal secretion and adipose metabolism under the influence of heat stress in dairy cattle. Therefore, alterations in glucose metabolism have negative consequences for the animal’s health, production, and reproduction under heat stress. Lactose is a major sugar of milk which is affected by the reshuffle of the whole-body energetic metabolism during heat stress, contributing towards milk production losses. Glucose homeostasis is maintained in the body by one of the glucose transporters’ family called facilitative glucose transporters (GLUTs encoded by SLC2A genes). Besides the glucose level, the GLUTs expression level is also significantly changed under the influence of heat stress. This review aims to describe the effect of heat stress on systemic glucose metabolism, facilitative glucose transporters, and its consequences on health and milk production.

Understanding the biological mechanisms of climatic adaptation is of paramount importance for the optimization of breeding programs and conservation of genetic resources. The aim of this study was to investigate genetic diversity and unravel genomic regions potentially under selection for heat and/or cold tolerance in thirty-two worldwide cattle breeds, with a focus on Chinese local cattle breeds adapted to divergent climatic conditions, Datong yak (Bos grunniens; YAK), and Bali (Bos javanicus) based on dense SNP data. In general, moderate genetic diversity levels were observed in most cattle populations. The proportion of polymorphic SNP ranged from 0.197 (YAK) to 0.992 (Mongolian cattle). Observed and expected heterozygosity ranged from 0.023 (YAK) to 0.366 (Sanhe cattle; SH), and from 0.021 (YAK) to 0.358 (SH), respectively. The overall average inbreeding (±SD) was: 0.118 ± 0.028, 0.228 ± 0.059, 0.194 ± 0.041, and 0.021 ± 0.004 based on the observed versus expected number of homozygous genotypes, excess of homozygosity, correlation between uniting gametes, and runs of homozygosity (ROH), respectively. Signatures of selection based on multiple scenarios and methods (F_ST, HapFLK, and ROH) revealed important genomic regions and candidate genes. The candidate genes identified are related to various biological processes and pathways such as heat-shock proteins, oxygen transport, anatomical traits, mitochondrial DNA maintenance, metabolic activity, feed intake, carcass conformation, fertility, and reproduction. This highlights the large number of biological processes involved in thermal tolerance and thus, the polygenic nature of climatic resilience. A comprehensive description of genetic diversity measures in Chinese cattle and YAK was carried out and compared to 24 worldwide cattle breeds to avoid potential biases. Numerous genomic regions under positive selection were detected using three signature of selection methods and candidate genes potentially under positive selection were identified. Enriched function analyses pinpointed important biological pathways, molecular function and cellular components, which contribute to a better understanding of the biological mechanisms underlying thermal tolerance in cattle. Based on the large number of genomic regions identified, thermal tolerance has a complex polygenic inheritance nature, which was expected considering the various mechanisms involved in thermal stress response.

The objectives of the present study were to identify key genes and biological pathways associated with thermal stress in Chinese Holstein dairy cattle. Hence, we constructed a cell-model, applied various molecular biology experimental techniques and bioinformatics analysis. A total of 55 candidate genes were screened from published literature and the IPA database to examine its regulation under cold (25°C) or heat (42°C) stress in PBMCs. We identified 29 (3 up-regulated and 26 down-regulated) and 41 (15 up-regulated and 26 down-regulated) significantly differentially expressed genes (DEGs) (fold change ≥ 1.2-fold and P < 0.05) after cold and heat stress treatments, respectively. Furthermore, bioinformatics analyses confirmed that major biological processes and pathways associated with thermal stress include protein folding and refolding, protein phosphorylation, transcription factor binding, immune effector process, negative regulation of cell proliferation, autophagy, apoptosis, protein processing in endoplasmic reticulum, estrogen signaling pathway, pathways related to cancer, PI3K- Akt signaling pathway, and MAPK signaling pathway. Based on validation at the cellular and individual levels, the mRNA expression of the HIF1A gene showed upregulation during cold stress and the EIF2A, HSPA1A, HSP90AA1, and HSF1 genes showed downregulation after heat exposure. The RT-qPCR and western blot results revealed that the HIF1A after cold stress and the EIF2A, HSPA1A, HSP90AA1, and HSF1 after heat stress had consistent trend changes at the cellular transcription and translation levels, suggesting as key genes associated with thermal stress response in Holstein dairy cattle. The cellular model established in this study with PBMCs provides a suitable platform to improve our understanding of thermal stress in dairy cattle. Moreover, this study provides an opportunity to develop simultaneously both high-yielding and thermotolerant Chinese Holstein cattle through marker-assisted selection.

The genetic mechanisms underlying the cattle resilience to severe cold temperatures are still unknown. In this study, we observed that four blood biochemical parameters were significantly altered, i.e., blood adrenocorticotropic hormone (ACTH), triiodothyronine (T3), thyroxine (T4), and potassium (K⁺) after expose to − 32 °C for 3 h. This was observed using 105 healthy Sanhe heifers with similar weight (398.17 ± 34.06 kg) and age (19.30 ± 4.91 months). A total of 20 single nucleotide polymorphisms (SNPs) were identified in 5′-flanking region of the hsp70 gene in Sanhe cattle, while only 10 SNPs were segregating when comparing genetic variations between Sanhe cattle and 285 Chinese Holstein samples. Statistically significant associations between the genomic markers SNP-42⁻, SNP-105⁺, SNP-181⁺, and SNP-205⁺ with blood T3 and between SNP-105⁺ and blood T4 were observed by applying the general linear model procedure and Bonferroni t test. Furthermore, we demonstrated that the T alleles of SNP-42⁻ and SNP-205⁺ in the GC box and Kozak sequence of the hsp70 gene, respectively, significantly decreased the green fluorescent proteins activity in vitro GFP reporter assays. These findings suggest that these two SNPs are causative polymorphisms involved in the regulation of hsp70 promoter activity and might contribute to the observed association between the hsp70 gene and T3 and T4 levels in Sanhe cattle. Thus, hsp70 gene is a promising candidate gene to be validated in independent cattle populations and functional studies related to cold stress resilience in cattle.