Introduction

The incidence of cancer, therapeutic response, and overall survival of cancer patients differ between men and women (Henley et al. 2020; Islami et al. 2021). Males are generally more likely to develop cancer. The National Cancer Institute reported through the Surveillance Epidemiology and End Results (SEER) database that for all cancers combined in the United States from 2016 to 2020, the age-adjusted incidence rate (and 95% confidence interval) per 100,000 was 477.8 ± 0.7 for males and 412.8 ± 0.6 for females. The same data analysis for the cancer mortality rate was 177.5 ± 0.3 for males and 128.7 ± 0.2 for females. The sex disparity in cancer is not restricted to any country or region. For the year 2020, the Global Cancer Observatory GLOBOCAN database provided statistics for 36 cancer types across 185 countries, with an age-adjusted incidence rate of 222.0 for males and 186.0 for females. In 2020, the world’s cancer mortality rate was 120.8 for males and 84.2 for females. We present in Table 1 the incidence rates for major cancers based on sex. Males have higher incidence rates for many types of cancer.

Table 1 Comparison of sex-specific incidence rates (per 100,000) for selected cancers with a male-to-female ratio indicating male bias (in blue) versus female bias (in pink)
Full size table

The numbers reported in Table 1 include sex-specific reproductive cancer types, such as ovarian and prostate cancers. The common non-reproductive cancers include the types that have high male-to-female ratios: colorectal cancers, lung and liver, and non-Hodgkin lymphoma. The analysis of SEER 2020 (USA) identified Kaposi sarcoma as having the highest male-to-female incidence rate ratio. In addition to breast cancer, which is rare in males, only a few cancers are more common in females, which is similar to what was previously noted (Dorak and Karpuzoglu 2012). In the case of gallbladder and thyroid cancer types, the male-to-female incidence rate ratio is less than 1.0. Although lifestyles are known to contribute to these differences, genetics also play an important role, and the molecular mechanisms involved are largely unknown. Despite traditional beliefs that sex hormones and hormonal regulation are the main explanatory factors for sexual dimorphism in cancer, accumulating evidence suggests that additional genetic and epigenetic mechanisms are at play. However, the specific molecular and cellular mechanisms responsible for sexual dimorphisms in cancer incidence and therapeutic responses are still in the early stages of discovery (Sandovici et al. 2022).

Non-coding RNAs (ncRNAs; RNAs that do not encode proteins) play critical roles in gene regulation (Mattick and Makunin 2006; Nair et al. 2020). Long noncoding RNAs (lncRNAs) are larger than 200 nucleotides and are important building blocks of gene regulatory networks in all eukaryotes (Kopp and Mendell 2018; Rinn and Chang 2012; Yao et al. 2019). LncRNAs share many similarities to messenger RNA (mRNA), including transcription by RNA Polymerase II, and undergoing co- and post-transcriptional processing events such as splicing, 5′ cap**, and 3′ polyadenylation (Cuykendall et al. 2017; Mattick et al. 2023; Quinn and Chang 2016). The human genome encodes thousands of lncRNAs, which represent potentially key sources of gene regulatory adaptation (Djebali et al. 2012). Analyzing lncRNAs is challenging as they are often expressed at low levels. Some investigators consider lncRNAs to be transcriptional “noise”. Therefore, the functions for most lncRNAs remain obscure and their biological importance is disputed. With advances in whole-genome technologies, increasing research on lncRNAs has highlighted their important role in a wide range of cellular processes. LncRNAs participate in chromatin remodeling and transcription, splicing, translation, and processing, localizing, and stabilizing other RNAs (Mattick et al. 2023).

An important role for lncRNAs in tumor initiation and progression has been established in recent years (Bhan et al. 2017; Jiang et al. 2019). Their tissue-specific expression makes them attractive for diagnostic and therapeutic purposes. For instance, the lncRNA PCA3 (Prostate Cancer Antigen 3) is used as a diagnostic marker for prostate cancer, and it can be easily found in urine samples (Taheri et al. 2022); the lncRNA HOTAIR (HOX antisense intergenic RNA) is involved in hormone therapies resistant in breast cancer (Xue et al. 2021; Syrett et al. 2019; Viggiano et al. 2016; Yu et al. 2021). Age-acquired skewed X-inactivation has recently been linked to cancer incidence (Roberts et al. 2022).

X-inactivation is an epigenetic hallmark of mammalian development (Fang et al. 2019; Payer et al. 2011). Two X-chromosomes in a female cell activate the expression of the X-Inactivation-Specific Transcript (XIST). In females, XIST is an lncRNA of 17-kb long that causes transcriptional inactivation of one of the two X-chromosomes, and this effect persists in all somatic cells throughout their life. LncRNA XIST and its flanking regulatory lncRNAs genes such as JPX (Just Proximal of ** (SA) can be induced, thereby disrupting the targeted lncRNA’s function (Liu et al. 2017). Large genomic screens can also be performed using Antisense Oligo Nucleotide (ASO) and RNA interference (RNAi) (Yip et al. 2022). To identify cancer sex-specific lncRNAs, a screen in female and male cancer cell lines must be performed. A variety of phenotypes can be asserted, such as survival, proliferation, invasion, and migration. A major advantage of the genetic screen approach is the ability to identify genes involved in tumor progression and compare their impact on female and male cells. Using cell lines has the disadvantage of missing all aspects of the tumor microenvironment (TME) that could impact sex-specific gene regulation. Therefore, clinical validation of the findings is essential.

Summary

Personalized therapies make it increasingly important to take biological sex into account. This review shows that lncRNAs play a role in cancer progression with different outcomes based on the sex. The molecular mechanisms behind this dimorphism need to be understood. LncRNAs are promising therapeutic targets that can also be used as diagnostic tools. There are several pathways involving lncRNAs, including chromosome X inactivation, hormonal signaling, and immunity. However, it is important to note that these are all interconnected pathways. Indeed, it is well known that the immune system is dependent on the signaling of sex hormones’ signaling, and that some immune genes are expressed from the X chromosome, including TLR8 (Toll-like receptor 8), TLR7 (Toll-like receptor 7), and IRAK1 (Interleukin-receptor-associated kinase 1). Moreover, it is difficult to determine how lifestyle influences cancer sex disparities and how environmental factors interact with sex-specific lncRNAs in affecting cancer. For the lncRNAs highlighted in this review, however, further investigation is required to establish a causal relationship with cancer sex dimorphism. The identification of the molecular mechanisms underlying cancer sex dimorphism may lead to the development of more targeted and effective cancer treatment options for males and females. In addition to its scientific impact, the characterization of sex dimorphism-related lncRNA could also have a positive impact on communities disproportionately at risk or afflicted by cancer. As a result of improving cancer treatment, we could potentially reduce cancer-related health disparities and improve health outcomes overall.